Original article

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
(GBM) yield a large number of prognostic factors, including
patient, tumor, and treatment variables (1 –6). Patients with
GBM are usually treated with surgery followed by a combi-
nation of radiation therapy (RT) and chemotherapy (3 – 5).
Concerning the postoperative chemo-RT, patients must be
assigned to prognostically homogeneous subgroups when
clinical trials are designed or clinical trial results are
compared. Curran et al. (1), who established the recursive
partitioning analysis (RPA) criteria for the classification
of malignant astrocytomas, used pretreatment- and
treatment-related prognostic variables from the Radiation
Therapy Oncology Group (RTOG) database. Although
the reliability of the RTOG-RPA criteria for assessing the
prognosis was established (2), advanced diagnostic and
therapeutic developments have provided novel prognostic
factors (7– 14).
As a pretreatment variable, quantitative diffusion-
weighted (DW) magnetic resonance imaging (MRI) pro-
vides indirect tissue information based on the detection of

Acta Radiologica 2013; 54: 214– 220. DOI: 10.1258/ar.2012.120525

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 Can MRI-derived factors predict the survival in glioblastoma patients?
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a change in the random motion of water protons at the cel-
lular or physiologic level (7 –10). On oncologic images, the
apparent diffusion coefficient (ADC) is thought to be inver-
sely correlated with tumor cellularity and to be a useful
diagnostic biomarker (15 – 18). Areas with minimum ADCs
reflect the sites of highest cellularity within heterogeneous
tumors and these sites are diagnostically and prognostically
important; patients whose tumors manifest a low minimum
ADC tend to have a poor prognosis (8 – 10). Many neurosur-
geons advocate tumor resection as extensive as possible in
GBM patients, although there is continuing debate about
the appropriateness of aggressive surgical management
(11 –14). MRI performed within 72 h after surgery is
thought to yield reliable and accurate information on
residual tumors (19, 20). The appropriate timing of post-
operative MRI avoids contrast enhancement attributable to
the surgery and minimizes difficulties in interpreting the
results.
Elsewhere we documented the relationship between
extent of resection and progression pattern in GBM patients
(14). However, there were no information about the
RTOG-RPA criteria and survival curves. Therefore, we eval-
uated their prognostic factors and followed the patients for
at least 24 months. The purpose of this further investigation
was to validate the predictive value of pretreatment quanti-
tative DW-MRI and early postoperative MRI based on
RTOG-RPA criteria in GBM patients treated with post-
operative chemo-RT.
Material and Methods
Patients and treatment
Between January 2000 and September 2009, we delivered
postoperative chemo-RT to 151 patients with newly-
diagnosed GBM. Of these, 138 (82 boys/men, 56 girls/
women; age range, 6 –82 years; mean age, 59 years) fulfilled
our inclusion criteria of (a) a histopathologic diagnosis of
GBM based on World Health Organization criteria (21),
(b) the absence of histologically identified oligodendroglial
components, (c) the absence of other previous or concurrent
brain diseases, and (d) the availability for review of digital
data from longitudinal MRI examinations including
images obtained within 2 weeks before surgery, within
72 h after surgery, and at 1-month intervals thereafter. We
excluded 13 patients because longitudinal MRI data were
not available. Our institutional review board approved
this retrospective study.
The 138 patients were allocated into RTOG-RPA classes
III-VI based on age, Karnofsky performance scale (KPS),
neurologic function, mental status, and treatment status.
In RTOG-RPA criteria, GBM patients ,50 years of age
are split into classes III and IV by KPS of 90 – 100 and
,90. Patients aged 50 years are first split by KPS of
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
home or hospitalized) partition into classes IV – VI; mental
status (normal vs. abnormal) divides the patients with a
KPS of ,70 into class V and VI.
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215
The surgical option, resection or biopsy, was chosen by
neurosurgeons on the basis of the tumor location and the
patient’s performance status. All patients underwent post-
operative chemo-RT with a total dose of 60 Gy administered
by using conventional fractionation. Nitrosourea-based
chemotherapy was administered as concurrent chemo-RT
and postoperative adjuvant treatment. Thereafter, all
patients were followed by physical and neurologic examin-
ations and MRI. If disease progression was documented
based on follow-up studies, salvage surgery, additional
RT, and/or additional chemotherapy were considered.
MRI
Longitudinal MRI studies were carried out within 2 weeks
before surgery, within 72 h after surgery, and at 1-month
intervals thereafter. MRI studies were performed with
a 1.5-T superconducting imager (Magnetom Vision;
Siemens, Erlangen, Germany) until December 2006 (8, 16).
From January 2007 forward, scans were acquired on a
3.0-T superconducting imager (Magnetom Trio; Siemens
AG, Erlangen, Germany). We obtained axial T1-weighted
spin-echo (SE) (600/8.5 [repetition time msec/echo time
msec]), T2-weighted fast SE- (3600/96; echo train length 7),
and fluid-attenuated inversion-recovery (FLAIR) (9000/81/
2500 [repetition time msec/echo time msec/inversion time
msec], echo train length 15) sequences, and triplanar
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
images were acquired in the transverse plane by using a
spin-echo echo planar imaging sequence with diffusion
gradient encoding in three orthogonal directions. The par-
ameters for DW images were 3600/81 (repetition time
msec/echo time msec), 5-mm slice thickness, 1 mm inter-
slice gap, 128  128 matrix, 230 mm FOV, one acquisition,
and a b-value of 1000 sec/mm2. DW imaging was per-
formed before contrast-enhanced T1-weighted imaging.
The ADC values were calculated according to the formula
ADC ¼ 2[ln(Sb /S0)]/b, where Sb is the signal intensity
of the region of interest (ROI) obtained through three
orthogonally oriented DW- or diffusion trace images, S0 is
the signal intensity of the ROI acquired through reference
T2-weighted images, and b is the gradient b factor with
a value of 1000 s/mm2. ADC maps were calculated on a
pixel-by-pixel basis with software of the MRI unit.
Additionally, post-contrast 3D magnetization-prepared
rapid acquisition gradient-echo (MP-RAGE) sequences
(1900/4.7/900, 9 flip angle) were obtained at a section
thickness of 1.0 mm, 256 matrix, and 256 mm FOV.
Post-contrast T1-weighted SE- and 3D-MP-RAGE sequences
were acquired after a bolus injection of 0.1 mmol/kg
Gd-DTPA (Magnevist; Bayer HealthCare Pharmaceuticals,
Osaka, Japan).
Image interpretation
All images were transferred to a workstation (ViewR,
version 1.20.01; Yokogawa Electric Corporation, Tokyo,
Japan) using the digital imaging and communications in
216 H Nakamura et al.
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Table 1 Univariate analysis for progression-free and overall survival

PFS OS
Prognostic factor n (%) Median (months) P value Median (months) P value
Total 138 4.4 13.7
Age (years)
49 27 (20) 6.3 0.084 16.5 0.005
50 111 (80) 4.2 12.1
KPS score
90 –100 64 (46) 5.2 0.026 15.8 ,0.001
,90 74 (54) 4.1 11.6
Minimum ADC
0.93 43 (31) 5.5 0.004 18.0 ,0.001
,0.93 64 (46) 3.6 11.2
Unknown 31 (22) 4.8 16.5
Residual tumor
Absent 39 (28) 8.9 ,0.001 18.9 ,0.001
Present 99 (72) 3.1 11.7

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-
ment DW-MRI studies we excluded 31 patients and classi-
fied them as unknown; 10 because digital data were
unavailable, seven because of inadequate amounts of solid
tumor components, and 14 because there was MRI evidence
of intratumoral hemorrhage. The solid tumor components
on conventional- and DW-MRI studies, i.e. contrast
enhancement or restricted diffusion, were identified consen-
sually by two neuroradiologists (TH and MK, with 22 and
18 years of brain MRI experience, respectively) who were
blinded to clinical information. ADC values were measured
by manually placing ROIs within solid tumor components
on the ADC maps. The ROIs measuring 40– 60 mm2 were
carefully placed to avoid volume-averaging with cystic
and/or necrotic areas that affect ADC values. Observers
placed three to five ROIs on areas thought visually to be
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
gross residual tumor was identified by the neuroradiolo-
gists. Enhancement that was massive, nodular, or thicker
than 5 mm was designated as gross residual tumor,
but thin-linear enhancement was considered to indicate
normal dural appearance (20). Based on the surgical
option and the gross residual tumor, the surgical procedures
were classified as biopsy, partial resection (PR), and gross
total resection (GTR).
Statistical analyses
Overall survival (OS) was measured from the time of
surgery to the day of death or last follow-up. Follow-up
ranged from 1.7 to 83.0 months (median, 13.7 months).
Surviving patients were followed for more than 24
months. Progression-free survival (PFS) was measured
from the time of surgery to the day of disease progression
or last follow-up. We analyzed the relationship between
prognostic factors and PFS and OS. Prognostic factors
included the patient age (49 vs. 50 years), KPS (,90
vs. 90 –100), gross residual tumor ( present vs. absent), and
the minimum ADC. To compare survival curves based on
minimum ADC values, a cut-off value was chosen at
the highest possible sensitivity and specificity (maximal
Youden index defined as sensitivity plus specificity
minus 1) on receiver-operating characteristic (ROC) curves.
In our ROC analyses we used 12-month OS as a positive
criterion (22). We also applied RTOG-RPA criteria to vali-
date the predictive value of MRI-based factors, i.e. the
minimum ADC and the gross residual tumor. Survival
curves were calculated using the Kaplan-Meier method;
overall differences in the survival curves were examined
with the log-rank test. The multivariate Cox’s proportional
hazards model was used to adjust for the influence of prog-
nostic factors. Statistical analyses were performed with the
MedCalc program (version 9.2.1.0; MedCalc Software,
Mariakierke, Belgium). For all analyses, values of P , 0.05
were considered to denote significant differences.
Results
On pretreatment DW-MRI, the minimum ADC values of
all tumors ranged from 0.539 to 1.399  10 – 3 mm2/s
(mean + standard deviation, 0.902 + 0.189  10 – 3 mm2/s).
Of the 138 patients, 39 (28%) had undergone GTR,
70 (51%) were treated by PR, and 29 (21%) underwent
biopsy. Stratification by RTOG-RPA criteria placed 19
patients in class III, 42 in class IV, 64 in class V, and 13 in
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
surgery as a second-line treatment.
Median PFS and OS among all 138 patients were 4.4 and
13.7 months, respectively. Quantitative DW-MRI showed
that patients whose tumors manifested a low minimum
ADC tended to experience short PFS and OS. ROC analysis
resulted in a cut-off value of 0.93  10 – 3 mm2/s and area
under the curve (AUC) of 0.675.
Univariate analysis for PFS showed that the KPS score
(P ¼ 0.026), minimum ADC (P ¼ 0.004), and gross residual
tumor (P , 0.001) were significant prognostic factors
(Table 1); multivariate analysis confirmed that gross
residual tumor represented a substantial independent

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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

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218 H Nakamura et al.
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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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Fig. 3 Overall survival curves based on MRI-derived factors in 107 patients
with GBM. The patients were grouped 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 inter-
mediate risk group. Median overall survival for the low-, intermediate-, and
high-risk group was 28.2, 14.7, and 10.8 months, respectively (P , 0.001). In
31 of our 138 patients the minimum ADC was not determined
correspond to the most aggressive foci within hetero-
geneous tumors and these sites are diagnostically and prog-
nostically important (8 – 10, 15 –17). Although Yamasaki
et al. demonstrated that the minimum ADC obtained from
pretreatment DW-MRI was a useful clinical prognostic bio-
marker in 33 patients with GBM (10), other earlier studies
evaluated the prognostic value of the minimum ADC in
patients with malignant astrocytoma including not only
GBM but also anaplastic astrocytoma (8, 9). Considering
also the influence of the surgical status on the prognosis,
current study simultaneously validates the predictive
values of the minimum ADC and gross residual tumor in
GBM patients. Clinical trials for GBM need to take into
account these MRI findings. Furthermore, the MRI-derived
factors can help in selecting adjuvant strategies;
MRI-derived high-risk patients may require aggressive
treatments including RT-dose escalation.
There were some limitations to current retrospective
study. First, our interpretations of gross residual tumor on
early postoperative MRI and tumor progression on
follow-up studies were not always confirmed by histo-
pathology. Nevertheless, current study suggested that the
MRI-derived gross residual tumor can predict the survival
in GBM patients treated with postoperative chemo-RT.
The limitations of DW imaging are its poor spatial resol-
ution and the potential risk of image distortion. DW
imaging does not eliminate artifacts attributable to inhomo-
geneous structures such as the skull base bone and sinus air
and the ADC changes if cystic, necrotic, and/or hemorrha-
gic areas are present (23). Volume averaging and misregis-
tration on ADC maps also affect ADC measurements. To
avoid the effect of artifacts or ADC changes, we excluded
31 patients with unavailable digital data, inadequate solid
tumor components, or gross hemorrhage from our ADC
analysis. Similarly, hemorrhage and reduction of tumor
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219
volume after surgery affect ADC measurements. In this
study, therefore, we did not evaluate ADC values on post-
operative MRI.
To compare the prognosis based on the minimum ADC,
we previously evaluated 79 patients with malignant astrocy-
toma including anaplastic astrocytoma and GBM and
selected a cut-off value of 1.0  10 – 3 mm2/s for OS (8).
Higano et al. (9) who assessed the predictability of the
glioma grade and prognosis in 15 anaplastic astrocytomas
and 22 GBMs, preferred a cut-off value of 0.9  10 – 3
mm2/s for PFS. In this study, we chose 12-month OS as a
positive criterion and a cut-off value of 0.93  10 – 3 mm2/s.
Study designs, e.g. the population and the endpoints,
should affect the cut-off ADC value. Additionally, we
used MRI data acquired on 1.5-T and 3.0-T imagers.
Sasaki et al. (24) reported the difference of ADC value
between 1.5-T and 3.0-T imagers from the same vendor to
be only 3 – 5%. Although it is suggested that at 1.5 T or
greater, the ADC value is generally a reproducible and
reliable parameter, different MRI scanners and different
observers may result in variations in ADC measurements
(16, 25). Investigations are underway to resolve these
issues, especially in patients whose tumors manifest border-
line ADC values.
With respect to other factors that influence the prognosis,
the role of chemotherapy in tumor control must not be over-
looked. Chemotherapy with temozolomide (TMZ) has been
reported to improve the survival and quality of life of GBM
patients (3 –5). In the study period, however, we used TMZ
as second-line chemotherapy because of restrictions under
health insurance. Since October 2009, we have included
TMZ in our postoperative chemo-RT protocol. As this
drug may result in changes in PFS and OS, we included
only patients treated before October 2009. Nevertheless,
our OS was compatible with the findings of Stupp et al.
(3) and Combs et al. (4). We will consider treating patients
manifesting disease progression with additional chemother-
apy that includes TMZ. Other second-line therapies, e.g.
salvage surgery and additional RT, may also affect their
OS (12).
In conclusion, the minimum ADC on pretreatment
DW-MRI and gross residual tumor on MRI obtained
within 72 h after surgery can predict the survival in GBM
patients treated with postoperative chemo-RT. Although
MRI-derived factors are helpful in the adjuvant treatment
of these patients, patient, tumor, and treatment variables
must also be considered.
Conflict of interest: None.
ACKNOWLEDGEMENTS
This work was supported by a Grant-in-Aid for Scientific
Research (22591388).
REFERENCES
1 Curran WJ Jr, Scott CB, Horton J, et al. Recursive partitioning analysis of
prognostic factors in three Radiation Therapy Oncology Group
malignant glioma trials. J Natl Cancer Inst 1993;85:704 –10
220 H Nakamura et al.
.................................................................................................................................................
2 Scott CB, Scarantino C, Urtasun R, et al. Validation and predictive power
of Radiation Therapy Oncology Group (RTOG) recursive partitioning
analysis classes for malignant glioma patients: A report using RTOG
90– 06. Int J Radiat Oncol Biol Phys 1998;40:51 –5
3 Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with
concomitant and adjuvant temozolomide versus radiotherapy alone on
survival in glioblastoma in a randomised phase III study: 5-year analysis
of the EORTC-NCIC trial. Lancet Oncol 2009;10:459 –66
4 Combs SE, Wagner J, Bischof M, et al. Postoperative treatment of
primary glioblastoma multiforme with radiation and concomitant
temozolomide in elderly patients. Int J Radiat Oncol Biol Phys
2008;70:987 –92
5 Gerstein J, Franz K, Steinbach JP, et al. Postoperative radiotherapy and
concomitant temozolomide for elderly patients with glioblastoma.
Radiother Oncol 2010;97:382 – 6
6 Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis of
416 patients with glioblastoma multiforme: Prognosis, extent of
resection, and survival. J Neurosurg 2001;95:190 –8
7 Oh J, Henry RG, Pirzkall A, et al. 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 2004;19:546 –54
8 Murakami R, Sugahara T, Nakamura H, et al. Malignant supratentorial
astrocytoma treated with postoperative radiation therapy: Prognostic
value of pretreatment quantitative diffusion-weighted MR imaging.
Radiology 2007;243:493 –9
9 Higano S, Yun X, Kumabe T, et al. Malignant astrocytic tumors: Clinical
importance of apparent diffusion coefficient in prediction of grade and
prognosis. Radiology 2006;241:839 –46
10 Yamasaki F, Sugiyama K, Ohtaki M, et al. Glioblastoma treated with
postoperative radio-chemotherapy: prognostic value of apparent
diffusion coefficient at MR imaging. Eur J Radiol 2010;73:532 –7
11 Pichlmeier U, Bink A, Schackert G, et al. Resection and survival in
glioblastoma multiforme: An RTOG recursive partitioning analysis of
ALA study patients. Neuro Oncol 2008;10:1025 –34
12 McGirt MJ, Chaichana KL, Gathinji M, et al. Independent association of
extent of resection with survival in patients with malignant brain
astrocytoma. J Neurosurg 2009;110:156 – 62
13 Brown PD, Maurer MJ, Rummans TA, et al. A prospective study of
quality of life in adults with newly diagnosed high-grade gliomas:
Downloaded from acr.sagepub.com at Yale University Library on June 28, 2015
The impact of the extent of resection on quality of life and survival.
Neurosurgery 2005;57:495 – 504
14 Murakami R, Hirai T, Nakamura H, et al. Recurrence patterns of
glioblastoma treated with postoperative radiation therapy: Relationship
between extent of resection and progression-free interval. Jpn J Radiol
2012;30:193 –7
15 Sugahara T, Korogi Y, Kochi M, et al. Usefulness of diffusion-weighted
MRI with echo-planar technique in the evaluation of cellularity in
gliomas. J Magn Reson Imaging 1999;9:53 –60
16 Murakami R, Hirai T, Sugahara T, et al. Grading astrocytic tumors by
using apparent diffusion coefficient parameters: Superiority of a one-
versus two-parameter pilot method. Radiology 2009;251:838 –45
17 Murakami R, Hirai T, Kitajima M, et al. Magnetic resonance imaging of
pilocytic astrocytomas: Usefulness of the minimum apparent diffusion
coefficient (ADC) value for differentiation from high-grade gliomas.
Acta Radiol 2008;49:462 –7
18 Bode MK, Ruohonen J, Nieminen MT, et al. Potential of diffusion
imaging in brain tumors: a review. Acta Radiol 2006;47:585 – 94
19 Albert FK, Forsting M, Sartor K, et al. Early postoperative magnetic
resonance imaging after resection of malignant glioma: Objective
evaluation of residual tumor and its influence on regrowth and
prognosis. Neurosurgery 1994;34:45 –60
20 Ekinci G, Akpinar IN, Baltacioglu F, et al. Early-postoperative magnetic
resonance imaging in glial tumors: Prediction of tumor regrowth and
recurrence. Eur J Radiol 2003;45:99– 107
21 Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of
tumours of the central nervous system. Acta Neuropathol 2007;114:97 –109
22 Ballman KV, Buckner JC, Brown PD, et al. The relationship between
six-month progression-free survival and 12-month overall survival end
points for phase II trials in patients with glioblastoma multiforme.
Neuro Oncol 2007;9:29 –38
23 Roberts TP, Rowley HA. Diffusion weighted magnetic resonance
imaging in stroke. Eur J Radiol 2003;45:185 –94
24 Sasaki M, Yamada K, Watanabe Y, et al. Variability in absolute apparent
diffusion coefficient values across different platforms may be substantial:
A multivendor, multi-institutional comparison study. Radiology
2008;249:624 – 30
25 Brander A, Kataja A, Saastamoinen A, et al. Diffusion tensor imaging
of the brain in a healthy adult population: Normative values and
measurement reproducibility at 3 T and 1.5 T. Acta Radiol 2010;51:800 – 7