Genitourinar y Imaging Original Research

Song et al.
DWI to Assess Radiotherapy-Treated Prostate Cancer

Genitourinary Imaging
Original Research

Assessment of Response to
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Radiotherapy for Prostate

FOCUS ON:

Cancer: Value of Diffusion-

Weighted MRI at 3 T
Inyoung Song1 OBJECTIVE. The objective of our study was to investigate the changes of apparent dif-
Chan Kyo Kim1 fusion coefficient (ADC) values in prostate cancers before and after radiotherapy at 3 T us-
Byung Kwan Park1 ing a phased-array coil.
Won Park 2 MATERIALS AND METHODS. Forty-nine patients with biopsy-proven prostate can-
cer who received radiotherapy underwent diffusion-weighted imaging (DWI) at 3 T and were
Song I, Kim CK, Park BK, Park W included in the study. Biopsies in all patients were performed before the initial MRI exami-
nation (range, 1535 days before MRI; mean, 23.4 days). All 49 patients underwent DWI (b
values = 0 and 1,000 s/mm2) before and 15 months after the completion of radiotherapy. The
changes in ADC values were measured for cancers and benign tissues before and after thera-
py. Additionally, the changes in serum prostate-specific antigen (PSA) levels were evaluated
before and after therapy.
RESULTS. A total of 57 cancers (peripheral zone, n = 45; transition zone, n = 12) were
found in 46 patients. For the tumors, the mean ADC value after therapy (1.61 10 3 mm2 /s)
was increased compared with the mean ADC value before therapy (1.0 10 3 mm2 /s) (p <
0.001). After radiotherapy, the mean ADC values of benign peripheral zones and of benign
transition zones were statistically significantly decreased compared with those before radio-
therapy (p < 0.05). Before treatment, a significant difference of ADC values between the tu-
mors and benign tissues was found (p < 0.001), whereas there was no significant difference of
ADC values between them after treatment (p > 0.1). The median PSA level after therapy (0.49
ng/mL) was decreased compared with the median PSA level before therapy (20.0 ng/mL).
CONCLUSION. With the use of a 3-T MR scanner, our preliminary results suggest that
ADC values may be useful as an imaging biomarker for monitoring therapeutic response of
Keywords: 3-T MRI, apparent diffusion coefficient, prostate cancer to radiotherapy.
diffusion-weighted imaging, MRI, prostate cancer,
radiotherapy

DOI:10.2214/AJR.09.3557
Received August 31, 2009; accepted after revision
December 7, 2009.
1
Department of Radiology and Center for Imaging
Science, Samsung Medical Center, Sungkyunkwan
University School of Medicine, 50 Ilwon-dong,
Kangnam-gu, Seoul 135-710, Republic of Korea. Address
correspondence to C. K. Kim (chankyokim@skku.edu).
2
Department of Radiation and Oncology, Samsung
Medical Center, Sungkyunkwan University School of
Medicine, Seoul, Republic of Korea.
WEB
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AJR 2010; 194:W477W482
0361803X/10/1946W477
American Roentgen Ray Society
D
etermination of the serum pros-
tate-specific antigen (PSA) level
has been widely used for screen-
ing, diagnosis, determination of
prognosis, and selection of the appropriate
treatment for men with clinically localized
prostate cancer [14]. Radiotherapy for pros-
tate cancer is currently one of the common
treatment strategies if the cancer is detected
at an early stage and invasive surgical resec-
tion can be avoided [5, 6]. After radiothera-
py, monitoring PSA levels is used to deter-
mine the effectiveness of treatment as an
early and accurate surrogate. However, PSA
monitoring has been shown to have a limited
role in defining cancer cure within the first 5
years after radiotherapy because, although a
lower PSA nadir after radiotherapy has been
associated with cancer cure, the treatment
ultimately fails in 525% of patientseven
in those with the most optimal biochemical
response. In addition, the most appropriate
biochemical definitions of treatment failure
after radiotherapy remain controversial be-
cause of substantial differences in the diag-
nostic accuracies of biochemical levels for
predicting clinical outcome. Moreover, no
pattern of PSA kinetics after radiotherapy
has conclusively differentiated between local
and distant failure [79]. To the contrary, a
functional MR technique such as diffusion-
weighted imaging (DWI) may detect and lo-
calize prostate cancer before radiotherapy
and then may provide qualitative or quantita-
tive information for measuring therapeutic
response in patients with prostate cancer
during and after radiotherapy.
With the introduction of higher-field-strength
MR scanners and the parallel imaging tech-
nique for prostate MRI, DWI has been shown

AJR:194, June 2010 W477

 Song et al.

TABLE 1: Distributions of Gleason
Scores in 49 Patients
Gleason Score No. of Patients (n = 49)
4 3
5 0
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All patients underwent a transrectal sonogra-
phyguided biopsy within 5 weeks before radio-
therapy. Biopsies in all patients were performed
before the initial MRI examination (range, 1535
days; mean, 23.4 days). The median Gleason score
before therapy was 7 (range, 410). Table 1 pres-
size, 0.35 0.59 3 mm; slice number, 20; and ac-
quisition time of each plane, 4 minutes 22 seconds.
DW images were acquired in the axial plane
using the single-shot echo-planar imaging tech-
nique. The scanning parameters were as follows:
2,7402,750/8385; slice thickness, 3 mm; inter-

6 10
7 20
8 11
9 3
10 2 Clinical response was determined from mea-
to have several potential benefits for the as-
sessment of tumor localization and staging. In
comparison with the use of conventional MRI,
DWI can noninvasively show the changes of
cellularity in malignant tumors in the body;
apparent diffusion coefficient (ADC) maps
can show the mobility of water in tissues.
After the treatment of malignant tumors,
the cellularity and cell membrane integrity in
necrotic tumor cells are reduced and there is a
subsequent increase in water mobility, where-
as viable tumor cells restrict diffusion of wa-
ter molecules. To date, several clinical studies
on the usefulness of DWI as a measurement
of treatment response have been reported [10
13]. For the evaluation of changes of ADC
values after radiotherapy in localized prostate
cancer, to our knowledge, few investigations
have been reported [14]. Therefore, the pur-
pose of this study was retrospectively to in-
vestigate the changes of ADC values in pros-
tate cancers before and after radiotherapy at
3 T using a phased-array coil.
ents the distributions of Gleason scores. All MR
scans were obtained before the start of radiother-
apy and 15 months (mean, 3.5 months) after the
completion of therapy. Twenty-seven patients re-
ceived simultaneous hormone therapy.
surements of serum PSA levels. The mean serum
PSA level was 42.5 ng/mL (range, 4.25456 ng/
mL) before biopsy and 0.87 ng/mL (range, 0.34
1.4 ng/mL) after the completion of radiotherapy.
MR Techniques
All images were collected using a 3-T MR sys-
tem (Intera Achieva, Philips Healthcare) equipped
with a phased-array coil (six-channel). All patients
underwent DWI in addition to imaging studies us-
ing a routine prostatic MR protocol. Before un-
dergoing scanning, each patient received an intra-
muscular injection of 20 mg of butyl scopolamine
(Buscopan, Boehringer Ingelheim) to suppress
bowel peristalsis; no bowel preparation was per-
formed. T2-weighted turbo spin-echo images were
acquired in three orthogonal planes (axial, sagittal,
and coronal). The T2-weighted imaging parame-
ters were as follows: TR range/TE range, 2,690
3,800/8090; slice thickness, 3 mm; interslice
gap, 0.31 mm; 512 304 matrix; field of view
(FOV), 18 cm; number of signals acquired (NSA),
3; sensitivity-encoding (SENSE) factor, 2; voxel
slice gap, 1 mm; matrix, 112 110; FOV, 20 cm;
SENSE factor, 2; and NSA, 3. Diffusion-encoding
gradients were applied as a bipolar pair at b val-
ues of 0 and 1,000 s/mm 2 along the three orthogo-
nal directions of motion-probing gradients. ADC
maps were automatically constructed on a pixel-
by-pixel basis (0 and 1,000 s/mm 2). The acquisi-
tion time of DWI was within 2 minutes.
Data Analysis and ADC Measurement
All images were retrospectively analyzed in
consensus by two genitourinary radiologists with
6 and 3 years of experience, respectively, who were
aware of the clinical and histologic findings. Each
reader had completed a genitourinary fellowship
and had interpreted more than 700 MR examina-
tions of the prostate at the time of the study.
The localization of prostate cancer was deter-
mined by consensus of the two readers based on a
comparison of digital rectal examination findings,
the pathologic results of biopsies, and the presence
of a focal low-signal-intensity area in the periph-
eral zone and transition zone on ADC maps with
or without the use of T2-weighted images. ADC
maps were processed using workstation software
(PRIDE tool, Philips Healthcare). With the use of
MRIcro software (version 1.37, Rorden and Brett,
2000), ADC values in tumors and in the peripher-
al zone and transition zone of benign tissue before

Materials and Methods

Patients
The ethics committee of our institute approved
this study. Written informed consent was waived
because of the retrospective nature of the analysis.
Between January 2006 and May 2008, 49 patients
with biopsy-proven prostate cancer underwent ex-
ternal beam radiotherapy and MR examinations at
3 T before and after radiotherapy in our hospital.
The median patient age was 67.5 years (age range,
4281 years).
Radiotherapy was administered at 2 Gy/fraction
to a total dose of 6674 Gy (median dose, 70 Gy)
with the use of a 15-MV linear accelerator. Thir-
ty-nine patients were treated with the use of 3D A B
conformal radiotherapy to the prostate only or to Fig. 1On axial apparent diffusion coefficient (ADC) maps (TR/TE, 2,749/84; matrix, 112 110; b = 0 and
the prostate and seminal vesicles. In 10 patients, a 1,000 s/mm2), method of ADC value measurement using region of interest (ROI) in tumor (arrow) and benign
whole-pelvis irradiation dose of 46 Gy was admin- peripheral zone (arrowhead) is shown.
istered, and an additional 2028 Gy was adminis- A and B, ROI was drawn on left lobe of midgland before (A) and after (B) radiotherapy. Mean ADC of tumor
increased from 0.89 10 3 mm2 /s before radiotherapy to 1.48 10 3 mm2 /s after radiotherapy. Note ROI in
tered to the prostate only or to the prostate and sem- benign peripheral zone of right lobe. Mean ADC value of benign peripheral zone decreased from 1.82 10 3
inal vesicles using a cone-down boost technique. mm2 /s before therapy to 1.63 10 3 mm2 /s after radiotherapy.

W478 AJR:194, June 2010

 DWI to Assess Radiotherapy-Treated Prostate Cancer

TABLE 2: Results of Mean Apparent Diffusion Coefficient (ADC) Values of 57

Tumors in 46 Patients and Benign Tissues in 49 Patients Before and 2.6
After Radiotherapy
2.4
ADC Value 10 3 mm2 /s, mean SD (range)
2.2
Time of ADC Measurement Tumors Benign Tissues
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2.0
Before radiotherapy

ADC ( 103 mm2/s)

Overall 1.00 0.19 (0.731.58)a 1.8

Peripheral zone 1.03 0.20 (0.771.58)a 2.05 2.07 (1.582.72)b 1.6

Transition zone 0.88 0.13 (0.73,1.08)a 1.72 0.24 (1.242.27)b 1.4

After radiotherapy
1.2
Overall 1.61 0.27 (0.892.46)
1.0
Peripheral zone 1.62 0.29 (0.892.47) 1.77 0.27 (1.352.48)
0.8
Transition zone 1.57 0.18 (1.311.91) 1.59 0.23 (1.222.33)
aComparison of the mean ADC values of tumors before and after radiotherapy, p < 0.001. 0.6
bComparison of the mean ADC values of benign tissues before and after radiotherapy, p < 0.05.
Before After
Radiotherapy Radiotherapy

and after radiotherapy were calculated by place-
ment of regions of interest (ROIs) (Fig. 1). When
the ROIs were drawn, great care was taken to ex-
clude both the neurovascular bundle and the ure-
thra to reduce any error in ADC calculations.
Before radiotherapy, ROIs of the tumors in the
peripheral zone and transition zone were drawn
on ADC maps to include as much of the tumor
as possible. ADC values in tumors were assessed
twice in the same site, and the average was calcu-
lated. If a tumor was located in several imaging
slices of ADC maps, ADC values were measured
on each image of the ADC maps and the average
was calculated. Tumors with a transverse greatest
diameter of more than 0.5 cm were included to re-
duce false-positive findings. High-resolution T2-
weighted images corresponding to the ADC maps
were observed in the transverse orientation to as-
sist in the identification of the detailed anatomy
of the prostate. For measurement of ADC values
in the peripheral zone and transition zone of be-
nign tissue, ROIs at the contralateral side of the
tumor were selected. In three different sites of be-
nign tissue, ADC values were measured and the
average was calculated.
After the completion of radiotherapy, there was
no visible residual tumor in most cases, particular-
ly for patients with a good response. In this situa-
tion, the ROI was drawn on what was considered
the normal residual prostate by two radiologists
in consensus; usually the ROI was drawn in the
same area as that initially used in the pretherapy
MR examination. ROIs were assessed twice in the
same site, and the average was calculated. For be-
nign tissues, the ROIs were drawn on the same
area that was initially used in preradiotherapy im-
ages, and the average was calculated.
Before radiotherapy, the mean ROIs were 208
mm2 for tumors (range, 10979 mm 2) and 28 mm 2
for benign tissue (range, 1743 mm 2). After radio-
therapy, the mean ROIs were 97.4 mm2 for tumors
(range, 10404 mm 2) and 22 mm 2 for benign tis-
sue (range, 1432 mm 2).
Statistical Analysis
Statistical analysis was performed using SAS
software (version 8, SAS Institute). The paired
Students t test was used to compare the ADC val-
ues of tumors and benign tissues before and after
radiotherapy and to compare the mean PSA lev-
els before and after radiotherapy. The comparison
of mean ADC values of tumors and benign tis-
sues before radiotherapy was performed using the
paired Students t test. A correlation in the degree
of change between serum PSA levels and ADC
values was performed by use of Pearsons correla-
tion. Two-tailed tests were used to calculate all p
values. A p value of < 0.05 was considered statis-
tically significant.
Results
In 46 of 49 patients, 57 cancers (peripher-
al zone, n = 45; transition zone, n = 12) were
found; in the remaining three patients, all of
whom had a Gleason score of 4, no focal mass
was seen on ADC maps. On the ADC maps
obtained before therapy, the mean size of the
tumors was 2.2 cm (range, 0.83.2 cm).
In 57 tumors of 46 patients, the mean
ADC value before therapy was 1.0 10 3
mm2 /s, which is significantly lower than the
mean ADC value after therapy (1.61 10 3
mm2 /s) (p < 0.001) (Table 2). After the com-
pletion of radiotherapy, there was no visible
tumor in 42 patients. However, in the remain-
ing four patients who had one tumor each,
residual tumor was seen on ADC maps 15
months after the completion of radiotherapy.
Fig. 2Graph of change in apparent diffusion
coefficient (ADC) values in 57 prostate cancers
after radiotherapy. These data show statistically
significant increase in ADC values in all cases except
two cases because of increased water diffusion after
radiotherapy.
The mean ADC value of those tumors was
1.08 10 3 mm2 /s.
Of the four patients with residual tumors,
follow-up ADC maps obtained 7 months af-
ter the completion of radiotherapy showed
that residual tumor had disappeared in two
patients; however, in the other two patients
who had one tumor each, the mean ADC val-
ue did not increase after radiotherapy. There
was no change in one patient (from 0.96
10 3 before therapy to 0.96 10 3 mm2 /s af-
ter therapy) and a decrease in the other pa-
tient (from 1.04 to 0.89 10 3 mm2 /s) (Figs.
2 and 3). These two patients showed a de-
crease in PSA level (from 21.12 ng/mL be-
fore therapy to 3.2 ng/mL after therapy and
from 16.62 ng/mL before therapy to 12.09
ng/mL after therapy, respectively) and a con-
siderable rise in PSA level after the comple-
tion of radiotherapy.
Before radiotherapy, the mean ADC val-
ues of tumors in both the peripheral zone
and transition zone were statistically lower
than the corresponding values of benign tis-
sues (p < 0.001). After radiotherapy, a sig-
nificant difference of ADC values between
the tumors and benign tissues was not found
(p > 0.1) (Table 2). The mean ADC values of
the peripheral zone and transition zone of be-
nign tissue were statistically decreased com-
pared with the corresponding values before
radiotherapy (p < 0.05).

AJR:194, June 2010 W479

 Song et al.

1,000

100
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10

PSA (ng/mL)
1

0.1

0.01

A B
0.001
Before After
Radiotherapy Radiotherapy

Fig. 4Graph of change in serum prostate-specific

antigen (PSA) levels in 49 patients with prostate
cancer after radiotherapy. These data show
statistically significant decrease in all cases after
radiotherapy.

tate cancer increased statistically in both the

peripheral zone and transition zone after ra-
diotherapy. One potential explanation for this
change was that an increase of the ADC af-
ter radiotherapy might be correlated with cel-
lularity increases because of a decrease in
C D the size and number of neoplastic glands, al-
Fig. 363-year-old man with left-sided prostate cancer with extracapsular extension (prostate-specific though tumors might still exist [21]. The re-
antigen level: before radiotherapy, 16.62 ng/mL; after radiotherapy, 12.09 ng/mL). sults of our study for malignant tumors after
A and B, Before radiotherapy, axial T2-weighted fast spin-echo image (TR/TE, 3,680/80) (A) and apparent therapy were found to be equivalent to those
diffusion coefficient (ADC) map (2,749/84: matrix, 112 110; b = 0 and 1,000 s/mm2) (B) show prostate cancer
of previous studies for other malignant tu-
(arrows) of low signal intensity in left lobe. Mean ADC value of cancer was 1.04 10 3 mm2 /s.
C, After radiotherapy, axial T2-weighted fast spin-echo image (3,680/80) shows diffusely ill-defined area of low mors after treatment such as hepatocellular
signal intensity in both lobes. This finding is indeterminate for assessing residual cancer. carcinomas [22], rectal cancers [12], brain
D, After radiotherapy, axial ADC map (2,749/84: matrix, 112 110; b = 0 and 1,000 s/mm2) shows residual cancer tumors [10, 11], and breast cancers [13].
(arrows) of low signal intensity in left lobe. Mean ADC value of residual cancer was 0.89 10 3 mm2 /s. This
finding suggests poor response for treatment. Compared with the use of 1.5 T, the use
of 3 T has several advantages [23]. Theo-
Figure 4 shows the changes in PSA lev- in ADC values are inversely correlated with retically, the signal-to-noise ratio (SNR) in-
els before and after radiotherapy. The medi- changes in cellularity: Increases in ADC creased twofold on moving from 1.5 to 3 T,
an PSA level before therapy was 20.0 ng/mL, values reflect an increase in the mobility of and an increased SNR can be translated into
which is significantly higher than the median water through a decrease in cellular size or improvements in spatial, temporal, and spec-
PSA level after therapy of 0.49 ng/mL (p < number, and decreases in ADC values reflect tral resolution. A limited SNR at 1.5 T may
0.001). A correlation in the degree of chang- a decrease in free extracellular water by an impair MR sensitivity for subtle changes in
es between the PSA levels and ADC values increase of total cellular size or number, as ADC values of the prostate. The increase in
was not found (p > 0.05). can be seen with tumor progression, fibrosis, SNR from 3-T imaging enables either an in-
or edema [15, 20]. crease in spatial resolution or an increase in
Discussion Takayama et al. [14] recently reported that the SNR of the ADC maps, so a possible in-
DWI as a functional imaging technique ADC values of prostate cancer significant- crease in the accuracy of MRI for prostate
can measure the mobility of water within ly increased after radiotherapy. In our study, cancer localization and of the measurements
tissues in addition to depicting tumor size DWI performed at 3 T with a phased-array of ADC values in prostate cancers using
and shape [15]. To date, several studies have coil was used to evaluate the changes of ADC ROIs may be expected. Therefore, we think
shown that the ADC values of prostate can- values of prostate cancer before and after ra- that the potential measurement error for tu-
cer are lower than the ADC values of be- diotherapy. As in the previous study [14], our mor ADC values at 3 T might be lower than
nign noncancerous tissue [1619]. Changes results showed that the ADC values of pros- that at 1.5 T.

W480 AJR:194, June 2010

 DWI to Assess Radiotherapy-Treated Prostate Cancer
In our study, after undergoing radiothera-
py of prostate cancer, all patients except two
showed an increase in the mean ADC val-
ues of tumors in both the peripheral zone and
the transition zone. In the remaining two pa-
tients, each of whom had one tumor, an in-
Downloaded from www.ajronline.org by 103.213.131.210 on 07/07/17 from IP address 103.213.131.210. Copyright ARRS. For personal use only; all rights reserved
crease in the ADC values was not shown:
The ADC value of one tumor was slightly
decreased, and the ADC value of the remain-
ing tumor showed no change. As determined
at subsequent follow-up of the two patients,
local treatment had failed; the patients un-
derwent salvage high-intensity focused ultra-
sound ablation.
As compared with a previous study [14]
that showed no significant changes of ADC
values in benign prostate tissue after ra-
diotherapy, our results showed a statisti-
cally significant decrease in the ADC val-
ues for the peripheral zone and transition
zone of benign noncancerous tissue. After
radiotherapy, benign prostate tissue might
show histologic changes of acinar distortion
and atrophy as well as stromal fibrosis with
granulation tissue formation that may cause
a decrease of ADC values. Furthermore, a
decrease of ADC values in benign prostate
tissue after radiotherapy might result from
a decrease in the extracellular space due to
inflammatory swelling of cells associated
with radiotherapy.
Before radiotherapy, the ADC values of
prostate cancer in our study were lower than
the corresponding values of noncancerous be-
nign prostate tissue, as described in previous
investigations [1719, 24]. Lower ADC values
in prostate cancer reflect the restriction of wa-
ter mobility due to the dense, high cellularity
of prostate cancer. Thus, prostate cancer pos-
sibly showing a higher ADC value was auto-
matically excluded from this study because ac-
curate localization of the cancer on ADC maps
was not possible. In three patients in our study
who had Gleason score 4, the use of DWI
could not delineate localized prostate cancer
and ADC values could not be measured.
In our study, the mean ROIs for tumors
and benign tissue were different before and
after radiotherapy. The reason is that the size
and volume of the prostate were markedly
decreased after radiotherapy as compared
with before radiotherapy.
There are several limitations to this study.
First, we did not perform frequent follow-
up MR examinations in all patients. Patients
underwent MR examinations before radio-
therapy and 15 months after radiotherapy.
As shown in previous studies of other body
AJR:194, June 2010 W481
tumors, DWI findings can reflect cellular
changes in malignant tissues earlier than 15
months after therapy, as early as 24 hours af-
ter treatment. For future studies, earlier and
more frequent examinations should be per-
formed during and after radiotherapy to as-
sess the dynamic changes of ADC values.
Second, all patients underwent a transrectal
sonographyguided biopsy with the pretreat-
ment MR examinations, which might have
affected the ADC values in benign pros-
tate tissues due to hemorrhage or inflamma-
tory changes. Third, we could not evaluate
for any correlation between MR images and
histopathologic findings because we did not
obtain surgical specimens. With the use of
a preclinical animal study, a detailed corre-
lation between MR images and histopatho-
logic findings should be determined dur-
ing or after radiotherapy. Fourth, this study
was retrospective in design with the use of
some different parameters such as TR and
TE. These differences in imaging parame-
ters might have affected ADC values of tu-
mor and benign prostate tissues. Finally, the
images in our study were interpreted by con-
sensus of two readers instead of by separate
analyses. However, the aim of this study was
not to evaluate the diagnostic performance
for detecting localized cancer on DWI but
to determine ADC changes in prostate can-
cer and normal prostate tissue before and af-
ter radiotherapy using 3 T. Moreover, the in-
terreader agreement of MRI including DWI
is not perfect for the detection of localized
prostate cancer. Thus, the localization of
prostate cancer in this study was determined
by consensus of two readers.
In conclusion, with the use of a 3-T MR
scanner, our preliminary results suggest that
ADC values may be useful as an imaging bio-
marker for monitoring therapeutic responses of
prostate cancer to radiotherapy. However, larg-
er, more definitive studies with clinical end-
points such as early response assessment with-
in 7 days after the initiation of radiotherapy or
pretherapeutic prediction of biochemical fail-
ure after radiotherapy should be performed.
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