Glioblastoma treated with postoperative radio-chemotherapy: Prognostic value of apparent diffusion coefficient at MR imaging

doi:10.1016/j.ejrad.2009.01.013

European Journal of Radiology

Volume 73, Issue 3, March 2010, Pages 532-537

https://doi.org/10.1016/j.ejrad.2009.01.013 Get rights and content

Abstract

Purpose

To retrospectively evaluate whether the mean, minimum, and maximum apparent diffusion coefficient (ADC) of glioblastomas obtained from pretreatment MR images is of prognostic value in patients with glioblastoma.

Materials and methods

The institutional review board approved our study and waived the requirement for informed patient consent. Between February 1998 and January 2006, 33 patients (24 males, 9 females; age range 10–76 years) with supratentorial glioblastoma underwent pretreatment magnetic resonance (MR) imaging. The values of the mean, minimum, and maximum ADC (ADC_mean, ADC_MIN, and ADC_MAX, respectively) of each tumor were preoperatively determined from several regions of interest defined in the tumors. After surgical intervention, all patients underwent irradiation and chemotherapy performed according to our hospital protocol. The patient age, symptom duration, Karnofsky performance scale score, extent of surgery, and ADC were assessed using factor analysis of overall survival. Prognostic factors were evaluated using Kaplan–Meier survival curves, the log-rank test, and multiple regression analysis with the Cox proportional hazards model.

Results

Likelihood ratio tests confirmed that ADC_MIN was the strongest among the three prognostic factors. Total surgical removal was the most important predictive factor for overall survival (P < 0.01). ADC_MIN was also statistically correlated with overall survival (P < 0.05) and could be used to classify patients into different prognostic groups. Interestingly, ADC_MIN was also the strongest prognostic factor (P < 0.01) in the group of patients in whom total tumor removal was not possible.

Conclusion

The ADC_MIN value obtained from pretreatment MR images is a useful clinical prognostic biomarker in patients with glioblastoma.

Introduction

Glioblastoma is the most common malignant primary neoplasm of the central nervous system; median survival is approximately 1 year [1], [2]. Conventional magnetic resonance imaging (MRI) can yield information on the gross anatomic structure of glioblastoma, but it provides little functional information. Diffusion-weighted (DW) MRI enables the volumetric intravoxel measurement of tissue characteristics based on the detection of changes in the random motion of water protons at the cellular or physiological level [3]. Although the usefulness of DW-MRI for preoperative grading and postoperative assessment of glial tumors has been investigated [4], [5], [6], [7], its value for predicting survival has not been fully addressed [8], [9], [10]. Because the apparent diffusion coefficient (ADC) is inversely related to tumor cellularity and the glioma grade [4], [6], [11], [12], [13], [14], we postulated that it reflects the biological viability and prognosis of glioblastomas. We therefore analyzed the ADC with respect to the surgical resection status and compared the mean, minimum, and maximum ADC (ADC_mean, ADC_MIN, and ADC_MAX, respectively) values as factors reflecting biological activity. We performed a retrospective study to determine whether these values obtained on preoperative MRI scans are of prognostic value in patients with glioblastoma. We discovered that the ADC_MIN value is a prognostic factor for survival in patients with glioblastomas that are not totally resectable.

Section snippets

Materials and methods

The institutional review board of our hospital approved this retrospective study and waived the requirement for informed patient consent. Patient information was kept confidential by removing all identifiers from our records at the completion of our analyses.

Patients, diagnosis and treatment

Between February 1998 and January 2006, 49 patients (29 males, 20 females) with histologically confirmed supratentorial glioblastoma were treated at our institution. Of these, 16 were excluded from this study for reasons such as incomplete MRI, progression from anaplastic or low-grade glioma, infratentorial tumors, and incomplete- or no postoperative irradiation or chemotherapy. The remaining 33 patients (24 males, 9 females; age range 10–76 years) with new, histologically confirmed

MRI study and image interpretation

All MRI scans were performed using a 1.5-T superconducting system (Signa Horizon; GE Medical Systems, Milwaukee, WI, USA) with a circularly polarized head coil. All patients underwent MRI studies that included at least unenhanced and contrast-enhanced transverse T1-weighted-, unenhanced transverse T2-weighted-, unenhanced transverse fluid-attenuated inversion-recovery (FLAIR)-, and unenhanced transverse DW images. The transverse T1-weighted spin–echo MR sequence was performed using the

Statistical analyses

Survival was measured from the time of operation to the time of death or last follow-up (range, 3.6–54.4 months; median, 16.6 months). Of the 33 patients, 6 were alive at the time of the latest follow-up. We used the median of ADC_mean, ADC_MIN, and ADC_MAX as the cutoff value. We also applied a categorization cutoff of 1.0 × 10⁻³ mm²/s because earlier studies used this value [4], [10]. We analyzed the relationship between patient survival and prognostic factors determined from clinical and MRI data.

Patient characteristics and imaging

The patients ranged in age from 10 to 76 years (mean ± standard deviation (S.D.): 57.3 ± 16.3; median 62). The KPS scores were 30 and 50 in 1 patient each, 60 and 70 in 4 each, 80 in 11, 90 in 9, and 100 in 3 patients. Surgery consisted of biopsy (n = 6), partial- (n = 12), subtotal- (n = 8), and total (n = 7) tumor removal. The ADC_mean of all tumors ranged from 0.716 × 10⁻³ to 1.389 × 10⁻³ mm²/s (mean ± S.D. 1.070 ± 0.141 × 10⁻³ mm²/s; median 1.066 × 10⁻³ mm²/s). The ADC_MIN ranged from 0.676 × 10⁻³ to 1.260 × 10⁻³ mm²/s (mean

Discussion

Our results suggest that the ADC value of tumors, obtained from preoperative MRI scans, represents a prognostic factor in patients with glioblastoma. Although ADC_mean, ADC_MIN, and ADC_MAX were statistically significant prognostic factors in our patients, we confirmed that ADC_MIN was the most sensitive predictive factor for the overall survival of these patients. Others [9], [10] who assessed the value of the ADC for predicting the prognosis of patients with malignant astrocytic tumors used ADC_MIN

Conclusions

The ADC_MIN value of tumors obtained from preoperative MR images is a useful clinical prognostic biomarker for overall survival in patients with glioblastoma. Patients whose tumors have a low minimum ADC (≤1.0 × 10⁻³ mm²/s) may have a poor prognosis, especially when the tumor cannot be completely resected. Thus, pretreatment DW-MRI and calculating the ADC values may be helpful for planning therapy in patients with glioblastoma.

Conflicts of interest

None.

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In this study, the mean ADC value of solid portions was 0.744 × 10−3 mm2/s, which was similar to a previous investigation of a C6 rat glioma-bearing model on an 11.7 tesla animal MR unit (18). In human glioblastoma, this value was reported to vary from 1.05-1.324 × 10−3 mm2/s (26-28), and the mean ADC value was obviously lower than that of human glioblastoma. The minimal ADC value of solid portions in this study was similar to that in a previous animal study on C6 rat glioma (29) and was still markedly lower than that value in human glioblastomas (in human glioblastomas, these values were reported to range from 0.673-0.934 × 10−3 mm2/s) (23,26,27,30).
To determine the association of the apparent diffusion coefficient (ADC) with quantitative cellularity and the nuclear-to-cytoplasmic ratio in C6 glioma.
Animal models bearing C6 gliomas underwent MR scans with T1 rapid acquisition with relaxation enhancement (RARE), T2 RARE, and high-resolution diffusion-weighted imaging sequences. For each model, three consecutive sections were used to draw regions of interest (ROIs) and measure ADC values; the middle section was localized in the plane with the maximal solid tumor area. The minimal, mean, and maximal ADC values were recorded for each ROI. GFAP-immunostained sections coregistered with ADC measurements were used to calculate tumor cellularity and the nuclear-to-cytoplasmic (N/C) ratio. Spearman's correlation was used to assess the relationship between ADC values and quantitative tumor cellularity as well as N/C ratios with a significance level of p < 0.05.
Thirty-three sections from 11 glioma-bearing rats were analyzed. The median values of the minimal, mean, and maximal ADC were 0.443 × 10⁻³, 0.744 × 10⁻³, and 1.140 × 10⁻³ mm²/s, respectively. The median cellularity and N/C ratio were 2151.234 per 0.025 mm² and 0.857, respectively. The minimal, mean, and maximal ADCs were all significantly associated with cellularity, with correlation coefficients of -0.712 (p < 0.001), -0.631 (p < 0.001), and -0.460 (p = 0.007), respectively. The minimal and mean ADC had significant negative relationships with the N/C ratio, with correlation coefficients of -0.565 (p =  0.001) and -0.426 (p = 0.013), respectively.
The minimal ADC correlated well with cellularity and N/C ratios in C6 glioma and may be used as a biomarker of these two pathological features.
Apparent Diffusion Coefficient Can Predict Response to Chemotherapy of Liver Metastases in Colorectal Cancer
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Most reports in the literature concerning CRC metastases suggest that lower pretreatment ADC tumor values are associated with better treatment response (8,9). Comparable observations were made concerning glioblastoma, malignant astrocytoma and primary central nervous system lymphoma that a lower pretreatment ADC correlates with improved survival (37–39). Necrotic lesions with higher pretreatment ADC values generally appear less susceptible to chemotherapy (8,9,40,41).
The aim of this meta-analysis was to evaluate the suitability of apparent diffusion coefficient (ADC) as a predictor of response to systemic chemotherapy in patients with metastatic colorectal carcinoma (CRC).
MEDLINE library, SCOPUS database, and EMBASE database were screened for relationships between pretreatment ADC values of hepatic CRC metastases and response to systemic chemotherapy. Overall, five eligible studies were identified. The following data were extracted: authors, year of publication, study design, number of patients, mean value ADC and standard-deviation, measure method, b-values, and Tesla-strength. The methodological quality of every study was checked according to the Quality Assessment of Diagnostic Studies-2 instrument. The meta-analysis was undertaken by employing RevMan 5.3 software. DerSimonian and Laird random-effects models with inverse-variance weights were used to account for heterogeneity. Mean ADC values including 95% confidence intervals were calculated.
Five studies (n = 114 patients) were included. The pretreatment mean ADC in the responder group was 1.15 × 10⁻³ mm²/s (1.03, 1.28) and 1.37 × 10⁻³ mm²/s (1.3, 1.44) in the nonresponder group. An ADC baseline threshold of 1.2 × 10⁻³ mm²/s, below which no nonresponder was found, can distinguish both groups.
The results indicate ADC can serve as a predictor of response to chemotherapy for CRC patients.
A Phase 2 Study of Dose-intensified Chemoradiation Using Biologically Based Target Volume Definition in Patients With Newly Diagnosed Glioblastoma
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We hypothesized that dose-intensified chemoradiation therapy targeting adversely prognostic hypercellular (TV_HCV) and hyperperfused (TV_CBV) tumor volumes would improve outcomes in patients with glioblastoma.
This single-arm, phase 2 trial enrolled adult patients with newly diagnosed glioblastoma. Patients with a TV_HCV/TV_CBV >1 cm³, identified using high b-value diffusion-weighted magnetic resonance imaging (MRI) and dynamic contrast-enhanced perfusion MRI, were treated over 30 fractions to 75 Gy to the TV_HCV/TV_CBV with temozolomide. The primary objective was to estimate improvement in 12-month overall survival (OS) versus historical control. Secondary objectives included evaluating the effect of 3-month TV_HCV/TV_CBV reduction on OS using Cox proportional-hazard regression and characterizing coverage (95% isodose line) of metabolic tumor volumes identified using correlative ¹¹C-methionine positron emission tomography. Clinically meaningful change was assessed for quality of life by the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire C30, for symptom burden by the MD Anderson Symptom Inventory for brain tumor, and for neurocognitive function (NCF) by the Controlled Oral Word Association Test, the Trail Making Test, parts A and B, and the Hopkins Verbal Learning Test–Revised.
Between 2016 and 2018, 26 patients were enrolled. Initial patients were boosted to TV_HCV alone, and 13 patients were boosted to both TV_HCV/TV_CBV. Gross or subtotal resection was performed in 87% of patients; 22% were O⁶-methylguanine-DNA methyltransferase (MGMT) methylated. With 26-month follow-up (95% CI, 19-not reached), the 12-month OS rate among patients boosted to the combined TV_HCV/TV_CBV was 92% (95% CI, 78%-100%; P = .03) and the median OS was 20 months (95% CI, 18-not reached); the median OS for the whole study cohort was 20 months (95% CI, 14-29 months). Patients whose 3-month TV_HCV/TV_CBV decreased to less than the median volume (3 cm³) had superior OS (29 vs 12 months; P = .02). Only 5 patients had central or in-field failures, and 93% (interquartile range, 59%-100%) of the ¹¹C-methionine metabolic tumor volumes received high-dose coverage. Late grade 3 neurologic toxicity occurred in 2 patients. Among non-progressing patients, 1-month and 7-month deterioration in quality of life, symptoms, and NCF were similar in incidence to standard therapy.
Dose intensification against hypercellular/hyperperfused tumor regions in glioblastoma yields promising OS with favorable outcomes for NCF, symptom burden, and quality of life, particularly among patients with greater tumor reduction 3 months after radiation therapy.
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All MRI studies were performed in either a 1.5-T (Signa Horizon; GE Medical Systems; Wisconsin, Waukesha, USA; before July 2007) or a 3-T super conducting system (Signa Excite HD 3.0T; GE Medical Systems; after July 2007). MRI were obtained as described previously.18,19 To summarize in brief, for the 3-T system, MRI scans obtained included T2WI (repetition time [TR] 4800 milliseconds, echo time [TE] 100 milliseconds, echo train length 18, field of view 22 × 22 cm, matrix size 512 × 320, NEX 2, section thickness 6 mm, intersection gap 1.0 mm, 1 acquisition), axial spin-echo T1WI (TR 450 milliseconds, TE 18 milliseconds, field of view 18 × 18 cm, matrix size 288 × 192, section thickness 6 mm, intersection gap 1.0 mm, 2 acquisitions).
Several intracranial pathologies present as a ring-enhancing lesion on conventional magnetic resonance imaging (MRI), creating diagnostic difficulty. We studied the characteristics of the anatomical border of gadolinium enhancement on T1-weighted imaging (WI) and hypointensity on T2WI to employ a simple technique of histogram-profile analysis of MRI for differentiation of various ring-enhancing intracranial lesions.
After approval from the institutional review board, preoperative MRI (T2WI, postcontrast T1WI) scans were analyzed retrospectively in 18 patients with histologically confirmed brain abscess, 66 glioblastomas, 46 brain-metastases, and 16 tumefactive multiple sclerosis (MS). T2WI and postcontrast T1WI were overlapped, and histogram-profile analysis was performed with in-house image-fusion software. The pattern of differential-peaks in histogram-profile was assessed visually. Kaplan–Meier survival analysis incorporating histogram-profile patterns was performed in patients with glioblastoma.
The histogram-profile study revealed 4 distinct patterns. Pattern 1 showed no differential T2-hypointensity trough, pattern 2 had T2-hypointensity trough inside, whereas pattern 3 had T2-hypointensity trough overlapping the enhanced margin. Pattern 4 had T2-hypointensity trough immediately external to the enhanced margin. Pattern 1 was specific for tumefactive MS (93.3%), whereas pattern 4 was specific for glioblastoma (40.7%). Pattern 4 glioblastoma was subdivided into rim (T2-hypointensity ≥50% of circumference of contrast-enhanced tumor) and arc (T2-hypointensity <50% of circumference of contrast-enhanced tumor). Pattern 4 glioblastoma was further subdivided into group A (edema: T2-hyperintensity ≥50% of circumference of contrast-enhanced tumor) and group B (less edema: T2-hyperintensity <50% of circumference of contrast-enhanced tumor). Patients with pattern 3 glioblastoma (37.6%) had better survival compared with others (P = 0.0341) and pattern 4B had decreased survival compared with pattern 4A (P = 0.0001) and others (P = 0.0003).
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Proton Magnetic Resonance Spectroscopy Detection of High Lipid Levels and Low Apparent Diffusion Coefficient Is Characteristic of Germinomas
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The MRI studies were done in 3 orthogonal planes and included nonenhanced T1-weighted images, T2-weighted images, fluid-attenuated inversion recovery images, and T2*-weighted images as described previously.14,15 Pre-gadolinium (Gd) enhanced DWI was performed with b values of 1000 under the condition as explained in a previous study.14,15 Transverse, sagittal, and coronal spin-echo T1-weighted images were acquired after the intravenous administration of a Gd-based contrast medium.
The differentiation of germinoma from other tumors by conventional magnetic resonance imaging (MRI) can be very difficult. The purpose of our study was to determine whether diffusion-weighted imaging (DWI) and single-voxel proton magnetic resonance spectroscopy (1H-MRS) could provide additional useful information for a definitive diagnosis of germinomas.
Our hospital's Institutional Review Board approved this retrospective study. We reviewed imaging studies of 26 patients with histologically confirmed germinomas who were treated at our hospital between 2003 and 2016. We also studied 25 patients with pineal tumors, which included 14 nongerminomatous germ cell tumors (NGGCTs), 9 pineal parenchymal tumors (PPTs; including 3 pineocytomas, 4 PPTs of intermediate differentiation [PPTID], and 2 pineoblastomas) and 2 meningiomas. Patients underwent conventional MRI and advanced MRI, including DWI and/or 1H-MRS.
The germinoma group comprised 24 males and 2 females, ranging in age from 9.1 to 37.7 years (average, 17.5 years; median, 14.6 years). The NGGCT group was all male, ranging in age from 5.4 to 51.9 years (mean, 20.1 years; median, 14.1 years). In the PPT group, patient age ranged from 4.5 to 64.7 years (mean, 29.9 years; median, 30.7 years). High lipid peaks detected on 1H-MRS were observed in 16 of 16 examined germinomas. In contrast, in the pineocytomas, PPTID, pineoblastomas, and meningiomas, lipid peaks were small or absent in 10 of 10 examined tumors. In the NGGCT group, high lipid peaks on 1H-MRS were observed in 11 of 12 examined tumors; however, no tumors showed high intensity on DWI, with all low to high mixed intensity. ADC was statistically lower in the germinoma group compared with the NGGCT group (P = 0.0002).
Lower ADC values and high lipid peaks detected on 1H-MRS are characteristics of germinomas.

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Glioblastoma treated with postoperative radio-chemotherapy: Prognostic value of apparent diffusion coefficient at MR imaging

Abstract

Purpose

Materials and methods

Results

Conclusion

Introduction

Section snippets

Materials and methods

Patients, diagnosis and treatment

MRI study and image interpretation

Statistical analyses

Patient characteristics and imaging

Discussion

Conclusions

Conflicts of interest

Lancet

Eur J Radiol

Neurobiol Aging

Brain tumors

N Engl J Med

MR imaging of high-grade cerebral gliomas: value of diffusion-weighted echoplanar pulse sequences

AJR Am J Roentgenol

Apparent diffusion coefficient of human brain tumors at MR imaging

Radiology

The added value of the apparent diffusion coefficient calculation to magnetic resonance imaging in the differentiation and grading of malignant brain tumors

J Comput Assist Tomogr

The role of diffusion-weighted imaging in patients with brain tumors

AJNR Am J Neuroradiol

Survival analysis in patients with glioblastoma multiforme: predictive value of choline-to-N-acetylaspartate index, apparent diffusion coefficient, and relative cerebral blood volume

J Magn Reson Imaging

Malignant astrocytic tumors: clinical importance of apparent diffusion coefficient in prediction of grade and prognosis

Radiology