Impact of [11C]Methionine Positron Emission Tomography for Target Definition of Glioblastoma Multiforme in Radiation Therapy Planning

doi:10.1016/j.ijrobp.2010.09.020

International Journal of Radiation OncologyBiologyPhysics

Volume 82, Issue 1, 1 January 2012, Pages 83-89

https://doi.org/10.1016/j.ijrobp.2010.09.020 Get rights and content

Purpose

The purpose of this work was to define the optimal margins for gadolinium-enhanced T₁-weighted magnetic resonance imaging (Gd-MRI) and T₂-weighted MRI (T₂-MRI) for delineating target volumes in planning radiation therapy for postoperative patients with newly diagnosed glioblastoma multiforme (GBM) by comparison to carbon-11-labeled methionine positron emission tomography ([¹¹C]MET-PET) findings.

Methods and Materials

Computed tomography (CT), MRI, and [¹¹C]MET-PET were separately performed for radiation therapy planning for 32 patients newly diagnosed with GBM within 2 weeks after undergoing surgery. The extent of Gd-MRI (Gd-enhanced clinical target volume [CTV-Gd]) uptake and that of T₂-MRI of the CTV (CTV-T₂) were compared with the extent of [¹¹C]MET-PET (CTV--[¹¹C]MET-PET) uptake by using CT--MRI or CT--[¹¹C]MET-PET fusion imaging. We defined CTV-Gd (x mm) and CTV-T₂ (x mm) as the x-mm margins (where x = 0, 2, 5, 10, and 20 mm) outside the CTV-Gd and the CTV-T₂, respectively. We evaluated the relationship between CTV-Gd (x mm) and CTV-- [¹¹C]MET-PET and the relationship between CTV-T₂ (x mm) and CTV-- [¹¹C]MET-PET.

Results

The sensitivity of CTV-Gd (20 mm) (86.4%) was significantly higher than that of the other CTV-Gd. The sensitivity of CTV-T₂ (20 mm) (96.4%) was significantly higher than that of the other CTV-T₂ (x = 0, 2, 5, 10 mm). The highest sensitivity and lowest specificity was found with CTV-T₂ (x = 20 mm).

Conclusions

It is necessary to use a margin of at least 2 cm for CTV-T₂ for the initial target planning of radiation therapy. However, there is a limit to this setting in defining the optimal margin for Gd-MRI and T₂-MRI for the precise delineation of target volumes in radiation therapy planning for postoperative patients with GBM.

Introduction

Glioblastoma multiforme (GBM) is the most common type of primary brain tumor in adults, and the treatment of GBM remains one of the most challenging endeavors in oncologic treatment. The current standard of care for newly diagnosed GBM is surgical resection, to the extent that it is feasible, followed by adjuvant radiotherapy and chemotherapy (1). Several studies over the past few decades have attempted to define the optimal radiation dose for GBM, yet the results have not been satisfying 2, 3, 4.

Highly accurate radiation therapy techniques such as stereotactic radiotherapy, radiosurgery, intensity-modulated radiotherapy, and proton therapy have recently developed. Improved survival by using such highly accurate radiation therapy is possible because high-dose irradiation to a limited target volume eradicates tumor cells while minimizing radiation exposure to normal, functional brain tissue. For this therapy to succeed, the first premise is that the extent of tumor must be correctly defined. Accurate definitions of the gross target volume (GTV) and the clinical target volume (CTV) are crucial.

To determine the radiation therapy treatment volume for GBM, many studies have used the enhanced area or peritumoral edema area on magnetic resonance imaging (MRI) or computed tomography (CT), respectively, to determine initial radiation treatment volume as well as boost volume 5, 6, 7. For instance, the method for target delineation of GBM at the University of Texas M. D. Anderson Cancer Center has been to define the CTV as the enhanced area (GTV) plus 2 cm and the planning target volume (PTV) as the CTV plus 0.5 cm (5). An alternate method, used by the Radiation Therapy Oncology Group (RTOG), is to define the initial field as the peritumoral edema plus 2 cm and the dose prescribed to this area is 46 Gy. The boost field is defined as the GTV plus 2.5 cm, and the dose prescribe to this area is 60 Gy 5, 6, 7. However, evidence for the margin of the enhanced area or the peritumoral edema of the GBM tumor is not sufficient (5).

Positron emission tomography (PET) has been used for 2 decades to assess the cerebral metabolism of patients with gliomas 8, 9. Carbon-11-labeled methionine PET ([¹¹C]MET-PET) plays an especially important role in improving diagnostic procedures for treating brain tumors (10). [¹¹C]Methionine is not taken up by normal brain tissue to a marked degree, and the sensitivity of [¹¹C]MET-PET for detecting glioma tumors appears to be high 11, 12, 13, 14, 15, 16. [¹¹C]MET-PET uptake by normal brain parenchyma is relatively low, and so [¹¹C]MET-PET shows promise for assessing cerebral tumor dimensions (17). It has been suggested that [¹¹C]MET-PET may more precisely outline the true extent of viable tumor tissue than MRI, whereas MRI has the capability to better delineate the total extent of associated pathologic changes, such as edema, in adjacent brain areas (18).

We undertook the present study of quantified results of [¹¹C]MET-PET and those of MRI to compare their abilities to delineate the extent of GBM and to show the implications of [¹¹C]MET-PET for treatment planning. Therefore, the extent of gadolinium (Gd) enhancement on T₁-weighted MRI and the high-intensity area on T₂-weighted MRI were compared with the extent of uptake of [¹¹C]MET-PET by using CT--MRI or CT--[¹¹C]MET-PET fusion imaging. We conducted this study to investigate the extent to which tumor growth was present and to quantify this growth in GBM by comparing MRI and [¹¹C]MET-PET. We assumed [¹¹C]MET-PET was the gold standard in this study for delineating the CTV, and we determined the optimal margins of Gd enhancement and high-intensity areas on T₂-weighted imaging. We evaluated the validity of the margins by comparison with those reported in a study by Jansen et al. (19), which correlated results of histopathologic observations with CT/MR images.

Section snippets

Methods and Materials

During the 2-year period between April 2006 and December 2008, 32 postoperative patients, newly diagnosed and histologically confirmed with GBM (Table 1), underwent stereotactic radiotherapy treatment planning at our department.

CT, Gd-enhanced T₁-weighted and T₂-weighted MRI, and [¹¹C]MET-PET were performed separately within 2 weeks after the 32 patients (18 men and 14 women; age range, 21-85 years; mean age, 64 years) underwent surgery. Steroid doses were not changed during the week in which

Results

The clinical characteristics and tumor locations of the 32 patients included in this study are given in Table 1. Patients were grouped according to the RTOG recursive partitioning analysis (RPA) class (21). Most patients were put into RPA class IV (n = 19), and smaller numbers were in classes VI (n = 8), III (n = 3), and V (n = 8).

Table 2 shows sensitivity, specificity, PPV, and NPV for CTV-Gd (x mm) and CTV-T₂ (x mm). The sensitivity of CTV-Gd (20 mm) (86.4%) was significantly higher than that

Discussion

Brain tumor tissue can be visualized with MRI and CT because of the increased water content (edema) compared with normal brain tissue and because of disruption of the blood--brain barrier, and the tumor tissue is visualized as contrast enhancement. However, neither contrast enhancement nor edema is always a real measure of the extent of tumor for gliomas. Tumor cells have been detected beyond the margins of contrast enhancement, in the surrounding edema and even in adjacent brain tissue that

Conclusion

It is necessary to use a margin of at least 2 cm in T₂-MRI for the initial target planning of radiation therapy. However, in radiation planning for postoperative patients with GBM, the CTV-Gd and CTV-T₂ margins differed considerably from that of CTV- [¹¹C]MET-PET. There is a limit to the optimal margin in this setting of the Gd-MRI and T₂-MRI. Thus, rather than using Gd-MRI and T₂-MRI, [¹¹C]MET-PET has promising potential for precisely delineating target volumes in planning radiation therapy

References (32)

Eric L. Chang et al.
Evaluation of peritumoral edema in the delineation of radiotherapy clinical target volumes for glioblastoma
Int J Radiat Oncol Biol Phys
(2007)
D.F. Nelson et al.
Hyperfractionated radiation therapy and bis-chlorethyl nitrosourea in the treatment of malignant glioma—possible advantage observed at 72.0 Gy in 1.2 Gy B.I.D. fractions: Report of the Radiation Therapy Oncology Group Protocol 8302
Int J Radiat Oncol Biol Phys
(1993)
R.C. Urtasun et al.
Survival improvement in anaplastic astrocytoma, combining external radiation with halogenated pyrimidines: Final report of RTOG 86-12, Phase I-II study
Int J Radiat Oncol Biol Phys
(1996)
E.P. Jansen et al.
Target volumes in radiotherapy for high-grade malignant glioma of the brain
Radiother Oncol
(2000)
E.C. Halperin et al.
Radiation therapy treatment planning in supratentorial glioblastoma multiforme: an analysis based on post mortem topographic anatomy with CT correlations
Int J Radiat Oncol Biol Phys
(1989)
P.J. Kelly et al.
Stereotactic histologic correlations of CT- and MRI-defined abnormalities in patients with glial neoplasms
Mayo Clin Proc
(1987)
Anca-Ligia Grosu et al.
l-(methyl-11C)Methionine positron emission tomography for target delineation in resected high-grade gliomas before radiotherapy
Int J Radiat Oncol Biol Phys
(2005)
R. Stupp et al.
Radiotherapy plus concomitant and adjuvant-temozolomide for glioblastoma
N Engl J Med
(2005)
D.F. Nelson et al.
Combined modality approach to treatment of malignant gliomas (re-evaluation of RTOG7401/ECOG 1374 with long-term follow-up. A joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group)
Natl Cancer Inst Monogr
(1988)
R. Stupp et al.
Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide
J Clin Oncol
(2002)

J.L. Chan et al.

Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy

J Clin Oncol

(2002)

G. Di Chiro et al.

Glucose utilization of cerebral gliomas measured by [¹⁸F]fluorodeoxyglucose and positron emission tomography

Neurology

(1982)

N.J. Patronas et al.

Glycolytic rate (PET) and contrast enhancement (CT) in human cerebral gliomas

Am J Nucl Res

(1983)

M. Bergstrom et al.

Discrepancies in brain tumor extent as shown by computed tomography and positron emission tomography using [68Ga]EDTA [¹¹C]glucose, and [¹¹C]methionine

J Comput Assist Tomogr

(1983)

J.M. Derlon et al.

[¹¹C]l-methionine uptake in gliomas

Neurosurgery

(1989)

A. Lilja et al.

Dynamic study of supratentorial gliomas with l-methyl-¹¹C-methionine and positron emission tomography

Am J Neuroradiol

(1985)

Cited by (56)

Dissociation Between 11C-Methionine-Positron Emission Tomography and Gadolinium-Enhanced Magnetic Resonance Imaging in Longitudinal Features of Glioblastoma After Postoperative Radiotherapy
2019, World Neurosurgery
Citation Excerpt :
This dose was prescribed using the 95% isodose line, which covered the GTV-1. The irradiation dose of the organs at risk (eye, optic nerve, and brain stem) was planned to be <5 Gy.18,19 Patients received concomitant TMZ at a dose of 75 mg/m2/day during the simultaneously integrated boost with hypofractionated IMRT, followed by adjuvant TMZ at a dose of 150–200 mg/m2/day for 5 days every 28 days, in accordance with the European Organization for Research and Treatment of Cancer–National Cancer Institute of Canada regimen,1 starting 1 month after RT completion.
The aims of the present study were to compare the longitudinal changes of glioblastoma multiforme after radiotherapy (RT) between 11C-methionine positron emission tomography (MET-PET) and gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) and to clarify whether these changes were predictive of survival. We included 30 patients, who had undergone MET-PET and Gd-MRI before and every 3 months after RT. The lesion/normal brain uptake (L/N) ratio and contrast-enhancing lesion volume were examined. The L/N ratio was decreased until 9 months after RT with significance until 3 months. The contrast-enhancing lesion volume was decreased until 3 months and thereafter increased until 9 months with significance. The variation rates of the L/N ratio between pre-RT and 3 months differentiated survival of >23 months from ≤23 months. A dissociation could exist in the longitudinal changes of GBM after RT between MET-PET and Gd-MRI. The variation rate of the L/N ratio could be related to survival.
Brain Tumors: An Update on Clinical PET Research in Gliomas
2017, Seminars in Nuclear Medicine
A previous review published in 2012 demonstrated the role of clinical PET for diagnosis and management of brain tumors using mainly FDG, amino acid tracers, and ¹⁸F-fluorothymidine. This review provides an update on clinical PET studies, most of which are motivated by prediction of prognosis and planning and monitoring of therapy in gliomas. For FDG, there has been additional evidence supporting late scanning, and combination with ¹³N ammonia has yielded some promising results. Large neutral amino acid tracers have found widespread applications mostly based on ¹⁸F-labeled compounds fluoroethyltyrosine and fluorodopa for targeting biopsies, therapy planning and monitoring, and as outcome markers in clinical trials. ¹¹C-alpha-methyltryptophan (AMT) has been proposed as an alternative to ¹¹C-methionine, and there may also be a role for cyclic amino acid tracers. ¹⁸F-fluorothymidine has shown strengths for tumor grading and as an outcome marker. Studies using ¹⁸F-fluorocholine (FCH) and ⁶⁸Ga-labeled compounds are promising but have not yet clearly defined their role. Studies on radiotherapy planning have explored the use of large neutral amino acid tracers to improve the delineation of tumor volume for irradiation and the use of hypoxia markers, in particular ¹⁸F-fluoromisonidazole. Many studies employed the combination of PET with advanced multimodal MR imaging methods, mostly demonstrating complementarity and some potential benefits of hybrid PET/MR.
Pre-irradiation tumour volumes defined by MRI and dual time-point FET-PET for the prediction of glioblastoma multiforme recurrence: A prospective study
2016, Radiotherapy and Oncology
The diagnostic accuracy of magnetic resonance imaging (MRI) for glioblastoma multiforme (GBM) is suboptimal. We analysed pre-treatment MRI- and dual time-point 18F-fluoroethylthyrosine-PET (FET-PET)-based target volumes and GBM recurrence patterns following radiotherapy with temozolomide.
Thirty-four patients with primary GBM were treated according to MRI-based treatment volumes (GTV_RM). Patients underwent dual time-point FET-PET scans prior to treatment, and biological tumour volumes (GTV_PET) were contoured but not used for target definition. Progressions were classified based on location of primary GTVs. Volume and uniformity of MRI- vs. FET-PET/CT-derived GTVs and progression patterns assessed by MRI were analysed.
FET-based GTVs measured 10 min after radionuclide injection (a.r.i.; median 37.3 cm³) were larger than GTVs measured 60 min a.r.i. (median 27.7 cm³). GTV_PET volumes were significantly larger than corresponding MRI-based GTVs. MRI and PET concordance for the identification of glioblastoma GTVs was poor (mean uniformity index 0.4). 74% of failures were inside primary GTV_PET volumes, with no solitary progressions inside the MRI-defined margin +20 mm but outside the GTV_PET detected.
The size and geometry of GTVs differed in the majority of patients. The GTV_PET volume depends on time after radionuclide injection. FET-PET better defined failure site than MRI alone.
11C-methionine positron emission tomography for target delineation of recurrent glioblastoma in re-irradiation planning
2018, Reports of Practical Oncology and Radiotherapy
Citation Excerpt :
When the irradiation is targeted to these CTVs, some part of the tumor would not be irradiated in most cases. The study in27 focused on patients with GBM receiving initial therapy; it is necessary to add at least a 2-cm margin for the high-intensity area on T2-weighted images. In this study, the sensitivity of the CTV-Gd was only 57%.
To define the optimal margin on MRI scans in the re-radiation planning of recurrent glioblastoma using methionine positron emission tomography (MET-PET).
It would be very useful if the optimal margin on MRI to cover the uptake area on MET-PET is known.
CT, MRI, and MET-PET were performed separately over the course of 2 weeks. Among the MRI scans, we used the contrast-enhanced T1-weighted images (Gd-MRI) and T2-weighted images (T2-MRI). The Gd-MRI-based clinical target volume (CTV) (CTV-Gd) and the T2-MRI-based CTV (CTV-T2) were defined as the contrast-enhanced area on Gd-MRI and the high intensity area on T2-MRI, respectively. We defined CTV x mm (x = 5, 10, 15, 20) as x mm outside the CTV. MET-PET-based CTV (CTV-MPET) was defined as the area of accumulation of MET-PET. We calculated the sensitivity and specificity of CTV-Gd and CTV-T2 following comparison with CTV-MPET, which served as the gold standard in this study.
The sensitivity of CTV-T2 5 mm (98%) was significantly higher than CTV-T2 (87%), and there was no significant difference in the sensitivity between CTV-T2 5 mm and CTV T2 10, 15, or 20 mm. The sensitivity of CTV-Gd 20 mm (97%) was lower than that of CTV-T2 5 mm (98%).
A margin of at least 5 mm around the high intensity area on T2-MRI is necessary in the target volume delineation of recurrent glioblastoma for the coverage of MET-PET findings in re-radiation therapy planning.
Radiomics for residual tumour detection and prognosis in newly diagnosed glioblastoma based on postoperative [11C] methionine PET and T1c-w MRI
2024, Scientific Reports
Loss of methylthioadenosine phosphorylase immunoreactivity correlates with poor prognosis and elevated uptake of 11C-methionine in IDH-mutant astrocytoma
2024, Journal of Neuro-Oncology

View all citing articles on Scopus

: Conflict of interest: none.

View full text

Clinical InvestigationImpact of [11C]Methionine Positron Emission Tomography for Target Definition of Glioblastoma Multiforme in Radiation Therapy Planning

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Methods and Materials

Results

Discussion

Conclusion

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Mayo Clin Proc

Int J Radiat Oncol Biol Phys

Radiotherapy plus concomitant and adjuvant-temozolomide for glioblastoma

N Engl J Med

Combined modality approach to treatment of malignant gliomas (re-evaluation of RTOG7401/ECOG 1374 with long-term follow-up. A joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group)

Natl Cancer Inst Monogr

Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide

J Clin Oncol

Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy

J Clin Oncol

Glucose utilization of cerebral gliomas measured by [18F]fluorodeoxyglucose and positron emission tomography

Neurology

Glycolytic rate (PET) and contrast enhancement (CT) in human cerebral gliomas

Am J Nucl Res

Discrepancies in brain tumor extent as shown by computed tomography and positron emission tomography using [68Ga]EDTA [11C]glucose, and [11C]methionine

J Comput Assist Tomogr

[11C]l-methionine uptake in gliomas

Neurosurgery

Dynamic study of supratentorial gliomas with l-methyl-11C-methionine and positron emission tomography

Am J Neuroradiol

Clinical Investigation
Impact of [¹¹C]Methionine Positron Emission Tomography for Target Definition of Glioblastoma Multiforme in Radiation Therapy Planning

Glucose utilization of cerebral gliomas measured by [¹⁸F]fluorodeoxyglucose and positron emission tomography

Discrepancies in brain tumor extent as shown by computed tomography and positron emission tomography using [68Ga]EDTA [¹¹C]glucose, and [¹¹C]methionine

[¹¹C]l-methionine uptake in gliomas

Dynamic study of supratentorial gliomas with l-methyl-¹¹C-methionine and positron emission tomography