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PENTING ! Can MRI-derived Factors Predict The Survival in Glioblastoma Patients Treated With Postoperative Chemoradiation Therapy
PENTING ! Can MRI-derived Factors Predict The Survival in Glioblastoma Patients Treated With Postoperative Chemoradiation Therapy
Hideo Nakamura1, Ryuji Murakami2, Toshinori Hirai3, Mika Kitajima3 and Yasuyuki Yamashita3
1
Department of Neurosurgery; 2Department of Medical Imaging; 3Department of Diagnostic Radiology, Faculty of Life Sciences,
Kumamoto University, Kumamoto, Japan
Correspondence to: Ryuji Murakami. Email: murakami@kumamoto-u.ac.jp
Abstract
Background: Advanced diagnostic and therapeutic developments may yield novel prognostic factors in
patients with glioblastoma multiforme (GBM).
Purpose: To validate the predictive values of pretreatment quantitative diffusion-weighted (DW) magnetic
resonance imaging (MRI) and MRI performed within 72 h after surgery in patients with GBM.
Material and Methods: Between January 2000 and September 2009, 138 patients with GBM underwent
postoperative chemoradiation therapy (chemo-RT) and longitudinal MRI before surgery, in the early
postoperative period, and at 1-month intervals thereafter. The role of the patient age, Karnofsky
performance scale (KPS) score, minimum apparent diffusion coefficient (ADC) on pretreatment DW-MRI,
and gross residual tumor on early postoperative MRI were assessed by factor analysis of overall survival
(OS). Survival curves were calculated using the Kaplan-Meier method; the multivariate Cox’s proportional
hazards model was used to adjust for the influence of prognostic factors. Radiation Therapy Oncology
Group-recursive partitioning analysis (RTOG-RPA) criteria were used to validate the predictive value of the
MRI-derived factors.
Results: Substantial independent prognostic factors were the KPS score (hazard ratio [HR], 1.812), minimum
ADC (HR, 2.365), and gross residual tumor (HR, 1.777). Based on MRI-derived factors, we assigned the
patients to different prognostic groups in the RTOG-RPA classification and grouped them according to the
level of risk, i.e. a high-risk group with low minimum ADCs (,0.93 10 – 3 mm2/s) with gross residual
tumor and a low-risk group with high minimum ADCs (0.93 10 – 3 mm2/s) without gross residual
tumor; the other patients were assigned to the intermediate-risk group. Median OS for the low-,
intermediate-, and high-risk groups were 28.2, 14.7, and 10.8 months, respectively (P , 0.001).
Conclusion: The minimum ADC on pretreatment DW-MRI and gross residual tumor on early postoperative
MRI can predict the survival in GBM patients treated with postoperative chemo-RT.
Keywords: Glioblastoma multiforme (GBM), prognosis, magnetic resonance imaging (MRI), apparent diffusion
coefficient (ADC), surgery
Submitted July 31, 2012; accepted for publication September 19, 2012
The heterogeneous nature of glioblastoma multiforme of malignant astrocytomas, used pretreatment- and
(GBM) yield a large number of prognostic factors, including treatment-related prognostic variables from the Radiation
patient, tumor, and treatment variables (1 –6). Patients with Therapy Oncology Group (RTOG) database. Although
GBM are usually treated with surgery followed by a combi- the reliability of the RTOG-RPA criteria for assessing the
nation of radiation therapy (RT) and chemotherapy (3 – 5). prognosis was established (2), advanced diagnostic and
Concerning the postoperative chemo-RT, patients must be therapeutic developments have provided novel prognostic
assigned to prognostically homogeneous subgroups when factors (7– 14).
clinical trials are designed or clinical trial results are As a pretreatment variable, quantitative diffusion-
compared. Curran et al. (1), who established the recursive weighted (DW) magnetic resonance imaging (MRI) pro-
partitioning analysis (RPA) criteria for the classification vides indirect tissue information based on the detection of
a change in the random motion of water protons at the cel- The surgical option, resection or biopsy, was chosen by
lular or physiologic level (7 –10). On oncologic images, the neurosurgeons on the basis of the tumor location and the
apparent diffusion coefficient (ADC) is thought to be inver- patient’s performance status. All patients underwent post-
sely correlated with tumor cellularity and to be a useful operative chemo-RT with a total dose of 60 Gy administered
diagnostic biomarker (15 – 18). Areas with minimum ADCs by using conventional fractionation. Nitrosourea-based
reflect the sites of highest cellularity within heterogeneous chemotherapy was administered as concurrent chemo-RT
tumors and these sites are diagnostically and prognostically and postoperative adjuvant treatment. Thereafter, all
important; patients whose tumors manifest a low minimum patients were followed by physical and neurologic examin-
ADC tend to have a poor prognosis (8 – 10). Many neurosur- ations and MRI. If disease progression was documented
geons advocate tumor resection as extensive as possible in based on follow-up studies, salvage surgery, additional
GBM patients, although there is continuing debate about RT, and/or additional chemotherapy were considered.
the appropriateness of aggressive surgical management
(11 –14). MRI performed within 72 h after surgery is
thought to yield reliable and accurate information on MRI
residual tumors (19, 20). The appropriate timing of post- Longitudinal MRI studies were carried out within 2 weeks
operative MRI avoids contrast enhancement attributable to before surgery, within 72 h after surgery, and at 1-month
the surgery and minimizes difficulties in interpreting the intervals thereafter. MRI studies were performed with
results. a 1.5-T superconducting imager (Magnetom Vision;
Elsewhere we documented the relationship between Siemens, Erlangen, Germany) until December 2006 (8, 16).
extent of resection and progression pattern in GBM patients From January 2007 forward, scans were acquired on a
(14). However, there were no information about the 3.0-T superconducting imager (Magnetom Trio; Siemens
RTOG-RPA criteria and survival curves. Therefore, we eval- AG, Erlangen, Germany). We obtained axial T1-weighted
uated their prognostic factors and followed the patients for spin-echo (SE) (600/8.5 [repetition time msec/echo time
at least 24 months. The purpose of this further investigation msec]), T2-weighted fast SE- (3600/96; echo train length 7),
was to validate the predictive value of pretreatment quanti- and fluid-attenuated inversion-recovery (FLAIR) (9000/81/
tative DW-MRI and early postoperative MRI based on 2500 [repetition time msec/echo time msec/inversion time
RTOG-RPA criteria in GBM patients treated with post- msec], echo train length 15) sequences, and triplanar
operative chemo-RT. contrast-enhanced T1-weighted SE sequences; the imaging
parameters were section thickness, 5 mm; intersection gap,
1 mm; 256 512 matrix, field of view (FOV) 230 mm. DW
Material and Methods images were acquired in the transverse plane by using a
spin-echo echo planar imaging sequence with diffusion
Patients and treatment gradient encoding in three orthogonal directions. The par-
Between January 2000 and September 2009, we delivered ameters for DW images were 3600/81 (repetition time
postoperative chemo-RT to 151 patients with newly- msec/echo time msec), 5-mm slice thickness, 1 mm inter-
diagnosed GBM. Of these, 138 (82 boys/men, 56 girls/ slice gap, 128 128 matrix, 230 mm FOV, one acquisition,
women; age range, 6 –82 years; mean age, 59 years) fulfilled and a b-value of 1000 sec/mm2. DW imaging was per-
our inclusion criteria of (a) a histopathologic diagnosis of formed before contrast-enhanced T1-weighted imaging.
GBM based on World Health Organization criteria (21), The ADC values were calculated according to the formula
(b) the absence of histologically identified oligodendroglial ADC ¼ 2[ln(Sb /S0)]/b, where Sb is the signal intensity
components, (c) the absence of other previous or concurrent of the region of interest (ROI) obtained through three
brain diseases, and (d) the availability for review of digital orthogonally oriented DW- or diffusion trace images, S0 is
data from longitudinal MRI examinations including the signal intensity of the ROI acquired through reference
images obtained within 2 weeks before surgery, within T2-weighted images, and b is the gradient b factor with
72 h after surgery, and at 1-month intervals thereafter. We a value of 1000 s/mm2. ADC maps were calculated on a
excluded 13 patients because longitudinal MRI data were pixel-by-pixel basis with software of the MRI unit.
not available. Our institutional review board approved Additionally, post-contrast 3D magnetization-prepared
this retrospective study. rapid acquisition gradient-echo (MP-RAGE) sequences
The 138 patients were allocated into RTOG-RPA classes (1900/4.7/900, 9 flip angle) were obtained at a section
III-VI based on age, Karnofsky performance scale (KPS), thickness of 1.0 mm, 256 matrix, and 256 mm FOV.
neurologic function, mental status, and treatment status. Post-contrast T1-weighted SE- and 3D-MP-RAGE sequences
In RTOG-RPA criteria, GBM patients ,50 years of age were acquired after a bolus injection of 0.1 mmol/kg
are split into classes III and IV by KPS of 90 – 100 and Gd-DTPA (Magnevist; Bayer HealthCare Pharmaceuticals,
,90. Patients aged 50 years are first split by KPS of Osaka, Japan).
70–100 vs. ,70. Among the patients with a KPS of 70–100,
surgery (resection vs. biopsy), RT dose (.54.4 vs. 54.4 Gy),
and neurologic function (able to work vs. confined to Image interpretation
home or hospitalized) partition into classes IV – VI; mental All images were transferred to a workstation (ViewR,
status (normal vs. abnormal) divides the patients with a version 1.20.01; Yokogawa Electric Corporation, Tokyo,
KPS of ,70 into class V and VI. Japan) using the digital imaging and communications in
ADC, apparent diffusion coefficient (10 – 3 mm2/s); KPS score, Karnofsky performance scale score; OS, overall survival; PFS, progression-free survival
medicine (DICOM) format. For ADC analysis of pretreat- minimum ADC values, a cut-off value was chosen at
ment DW-MRI studies we excluded 31 patients and classi- the highest possible sensitivity and specificity (maximal
fied them as unknown; 10 because digital data were Youden index defined as sensitivity plus specificity
unavailable, seven because of inadequate amounts of solid minus 1) on receiver-operating characteristic (ROC) curves.
tumor components, and 14 because there was MRI evidence In our ROC analyses we used 12-month OS as a positive
of intratumoral hemorrhage. The solid tumor components criterion (22). We also applied RTOG-RPA criteria to vali-
on conventional- and DW-MRI studies, i.e. contrast date the predictive value of MRI-based factors, i.e. the
enhancement or restricted diffusion, were identified consen- minimum ADC and the gross residual tumor. Survival
sually by two neuroradiologists (TH and MK, with 22 and curves were calculated using the Kaplan-Meier method;
18 years of brain MRI experience, respectively) who were overall differences in the survival curves were examined
blinded to clinical information. ADC values were measured with the log-rank test. The multivariate Cox’s proportional
by manually placing ROIs within solid tumor components hazards model was used to adjust for the influence of prog-
on the ADC maps. The ROIs measuring 40– 60 mm2 were nostic factors. Statistical analyses were performed with the
carefully placed to avoid volume-averaging with cystic MedCalc program (version 9.2.1.0; MedCalc Software,
and/or necrotic areas that affect ADC values. Observers Mariakierke, Belgium). For all analyses, values of P , 0.05
placed three to five ROIs on areas thought visually to be were considered to denote significant differences.
the minimum and maximum ADC regions, more ROIs for
more heterogeneous lesions. The minimum ADC values
were selected for analysis (16).
On early postoperative MRI, the presence or absence of
Results
gross residual tumor was identified by the neuroradiolo- On pretreatment DW-MRI, the minimum ADC values of
gists. Enhancement that was massive, nodular, or thicker all tumors ranged from 0.539 to 1.399 10 – 3 mm2/s
than 5 mm was designated as gross residual tumor, (mean + standard deviation, 0.902 + 0.189 10 – 3 mm2/s).
but thin-linear enhancement was considered to indicate Of the 138 patients, 39 (28%) had undergone GTR,
normal dural appearance (20). Based on the surgical 70 (51%) were treated by PR, and 29 (21%) underwent
option and the gross residual tumor, the surgical procedures biopsy. Stratification by RTOG-RPA criteria placed 19
were classified as biopsy, partial resection (PR), and gross patients in class III, 42 in class IV, 64 in class V, and 13 in
total resection (GTR). class VI. At the most-recent follow-up, 17 patients were
alive; five were free of disease progression. Among 133
patients with disease progression, 18 underwent salvage
Statistical analyses surgery as a second-line treatment.
Overall survival (OS) was measured from the time of Median PFS and OS among all 138 patients were 4.4 and
surgery to the day of death or last follow-up. Follow-up 13.7 months, respectively. Quantitative DW-MRI showed
ranged from 1.7 to 83.0 months (median, 13.7 months). that patients whose tumors manifested a low minimum
Surviving patients were followed for more than 24 ADC tended to experience short PFS and OS. ROC analysis
months. Progression-free survival (PFS) was measured resulted in a cut-off value of 0.93 10 – 3 mm2/s and area
from the time of surgery to the day of disease progression under the curve (AUC) of 0.675.
or last follow-up. We analyzed the relationship between Univariate analysis for PFS showed that the KPS score
prognostic factors and PFS and OS. Prognostic factors (P ¼ 0.026), minimum ADC (P ¼ 0.004), and gross residual
included the patient age (49 vs. 50 years), KPS (,90 tumor (P , 0.001) were significant prognostic factors
vs. 90 –100), gross residual tumor ( present vs. absent), and (Table 1); multivariate analysis confirmed that gross
the minimum ADC. To compare survival curves based on residual tumor represented a substantial independent
Table 2 Multivariate analysis for overall survival Table 4 Overall survival based on RTOG-RPA criteria and residual
tumor
Prognostic factor Hazard ratio (95% CI) P value
Present Absent Total
Age 50 years Not applicable Not applicable
KPS score ,90 1.812 (1.185, 2.771) 0.006 RTOG-RPA Median Median Median
Minimum ADC ,0.93 2.365 (1.482, 3.776) ,0.001 class n (months) n (months) n (months)
Biopsy/Partial resection 1.777 (1.073, 2.943) 0.026
III 12 16.6 7 16.4 19 16.6
IV 26 16.1 16 26.8 42 17.3
95% CI, 95% confidence interval; ADC, apparent diffusion coefficient
(10 – 3 mm2/s)
V 49 11.1 15 16.5 64 11.5
VI 12 7.5 1 18.3 13 8.6
Total 99 11.7 39 18.9 138 13.7
Table 3 Overall survival based on RTOG-RPA criteria and the
Residual tumor on early postoperative MRI
minimum ADC
RTOG-RPA, Radiation Therapy Oncology Group-recursive partitioning
<0.93 0.93 Unknown analysis
RTOG-RPA Median Median Median
class n (months) n (months) n (months)
Table 5 Overall survival based on MRI-derived factors in 107 GBM
III 5 13.7 6 30.5 8 29.1
patients
IV 18 13.7 16 20.1 8 22.8
V 30 10.1 20 15.6 14 11.2 Prognostic factor n Median (months) P value
VI 11 7.5 1 8.6 1 13.7 Presence of residual tumor
Total 64 11.2 43 18.0 31 16.5
Minimum ADC , 0.93 54 10.8 0.002
–3 2 Minimum ADC 0.93 24 14.6
Minimum apparent diffusion coefficient (ADC) value (10 mm /s)
RTOG-RPA, Radiation Therapy Oncology Group-recursive partitioning
Absence of residual tumor
analysis Minimum ADC , 0.93 10 15.2 0.038
Minimum ADC 0.93 19 28.2
prognostic factor (Hazard ratio [HR], 5.825; 95% confidence In 31 of our 138 patients the minimum ADC was not determined
ADC, apparent diffusion coefficient (10 – 3 mm2/s)
interval [CI], 3.315 –10.236; P , 0.001). For OS, the patient
age (P ¼ 0.005), KPS score (P ,0.001), minimum ADC
(P , 0.001), and gross residual tumor (P , 0.001) were sig-
MRI could be used to assign patients to different prognostic
nificant factors; substantial independent prognostic factors
groups within the existing RTOG-RPA classes. These
were the KPS score (HR, 1.812; 95% CI, 1.185 –2.771;
MRI-derived factors were independent prognostic factors
P ¼ 0.006), minimum ADC (HR, 2.365; 95% CI, 1.482 –
and also divided GBM patients into low-, intermediate-,
3.776; P , 0.001), and gross residual tumor (HR, 1.777;
and high-risk groups.
95% CI, 1.073 –2.943; P ¼ 0.026) (Table 2).
Elsewhere, we demonstrated the progress of gross
The minimum ADC on pretreatment DW-MRI and the
residual tumor in all (100%) biopsied tumors and 97%
gross residual tumor on early postoperative MRI could be
tumors subjected to PR; of the tumors subjected to GTR,
used to assign patients to established RTOG-RPA classes
62% recurred at the site of peritumoral edema represented
(Tables 3 and 4). Median OS among the RTOG-RPA
by hyperintensity on T2-weighted images and 26% recurred
classes with low and high minimum ADC values, respect-
at distant sites (14). Considering the recurrence pattern, the
ively, was 13.7 and 20.1 months for classes III and IV
surgical status was classified into presence and absence
(P ¼ 0.002) and 9.5 and 15.6 months for classes V and VI
of gross residual tumor in this further investigation.
(P ¼ 0.001). Median OS among the RTOG-RPA classes
Consequently, not only PFS but also OS was substantially
with gross residual tumor (biopsy or PR) and without
longer in patients without gross residual tumor. Similarly,
gross residual tumor (GTR), respectively, was 16.3 and
Pichlmeier et al. (11) who grouped patients based on
20.4 months for classes III and IV (P ¼ 0.048) and 10.1
RTOG-RPA criteria to eliminate selection bias, demon-
and 16.5 months for classes V and VI (P , 0.001). The
strated that classes IV and V patients without- survived sig-
minimum ADC and gross residual tumor could be used to
nificantly longer than patients with gross residual tumor;
divide the patients into different prognostic groups
median OS was 17.7 vs. 12.9 months for class IV and 13.7
(Table 5). Application of these MRI-derived factors resulted
vs. 10.4 months for class V patients without and with
in three classifications, i.e. high risk with low minimum
gross residual tumor, respectively. Because GTR is thought
ADCs and gross residual tumor (Fig. 1), low risk with
to prolong survival, tumor resection is as extensive as poss-
high minimum ADCs and no gross residual tumor
ible (11– 14). Formerly, the surgical status was classified
(Fig. 2), and intermediate (other parameters); the median
based on the chosen surgical option, resection or biopsy.
OS for patients in the low-, intermediate-, and high-risk
Advances in surgical and diagnostic techniques yielded
groups was 28.2, 14.7, and 10.8 months, respectively
GTR as a new status (11 – 14). We recommend that the
(P , 0.001) (Fig. 3).
surgical status be classified based on MRI studies performed
within 72 h after surgery, i.e. the presence or absence of
gross residual tumor.
Discussion The ADC is thought to be inversely correlated with tumor
We found that the minimum ADC on pretreatment cellularity and to be a useful diagnostic biomarker (15– 18).
DW-MRI and gross residual tumor on early postoperative It is believed that regions exhibiting the minimum ADC
Fig. 1 Longitudinal MRI studies in a 70-year-old woman with GBM (RTOG-RPA class V, MRI-derived high risk). (a) T2-weighted and (b) contrast-enhanced
T1-weighted MRI before surgery showed an enhancing tumor with a cystic component and peritumoral edema. (c) On DW image, the enhancing area manifests
high signal intensity. (d) On the ADC map, the minimum ADC in the enhancing area (arrow) is 0.610 10 – 3 mm2/s. (e) Early postoperative MRI demonstrated a
gross residual tumor (arrows); the surgical procedure was partial resection. (f ) Three months later we detected disease progression from the gross residual tumor.
This patient died 9 months after surgery
Fig. 2 Longitudinal MRI studies in a 74-year-old man with GBM (RTOG-RPA class V, MRI-derived low risk). (a) T2-weighted and (b) contrast-enhanced
T1-weighted MRI before surgery showed an enhancing tumor and peritumoral edema. (c) On DW image, the enhancing area manifests iso-signal intensity.
(d) On the ADC map, the minimum ADC in the enhancing area (arrow) is 1.252 10 – 3 mm2/s. (e) Early postoperative MRI demonstrated gross total resection
of the enhancing tumor. (f ) Thirteen months later there was disease progression from the wall of resection cavity (arrows). This patient survived under
salvage chemotherapy for 26 months after surgery
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