MRI findings in men on active surveillance for prostate cancer: does dutasteride make MRI visible lesions less conspicuous? Results from a placebo-controlled, randomised clinical trial
MRI f indings in men on active surveillance for prostate cancer: does dutasteride make MRI visible lesions less conspicuous? Results from a placebo-controlled, randomised clinical trial
Francesco Giganti 0 1 2 3 4 5 6 7 8 9 10
Caroline M. Moore 0 1 2 3 4 5 6 7 8 9 10
Nicola L. Robertson 0 1 2 3 4 5 6 7 8 9 10
Neil McCartan 0 1 2 3 4 5 6 7 8 9 10
Charles Jameson 0 1 2 3 4 5 6 7 8 9 10
Simon R. J. Bott 0 1 2 3 4 5 6 7 8 9 10
Mathias Winkler 0 1 2 3 4 5 6 7 8 9 10
Giulio Gambarota 0 1 2 3 4 5 6 7 8 9 10
Brandon Whitcher 0 1 2 3 4 5 6 7 8 9 10
Ramiro Castro 0 1 2 3 4 5 6 7 8 9 10
Mark Emberton 0 1 2 3 4 5 6 7 8 9 10
Clare Allen 0 1 2 3 4 5 6 7 8 9 10
Alex Kirkham 0 1 2 3 4 5 6 7 8 9 10
Francesco Giganti 0 1 2 3 4 5 6 7 8 9 10
0 1 2 3 4 5 6 7 8 9 10
0 Department of Urology, University College London Hospital NHS Foundation Trust , London , UK
1 Research and Development , GlaxoSmithKline, Philadelphia, PA , USA
2 Division of Surgery & Interventional Science, University College London , London , UK
3 Department of Radiology, University College London Hospital NHS Foundation Trust , 235 Euston Road, London NW1 2BU , UK
4 Department of Mathematics, Imperial College London , London , UK
5 Klarismo , London , UK
6 Université de Rennes 1, LTSI , Rennes F-35000 , France
7 INSERM, U1099 , Rennes F-35000 , France
8 Department of Urology, Charing Cross Hospital, Imperial College NHS Trust , London , UK
9 Department of Urology, Frimley Park Hospital , Surrey , UK
10 Department of Pathology, University College London Hospital NHS Foundation Trust , London , UK
Objectives To investigate changes in the Apparent Diffusion Coefficient (ADC) using diffusion-weighted imaging (DWI) in men on active surveillance for prostate cancer taking dutasteride 0.5 mg or placebo. Methods We analysed 37 men, randomised to 6 months of daily dutasteride (n = 18) or placebo (n = 19), undergoing 3T multi-parametric Magnetic Resonance Imaging (mpMRI) scans at baseline and 6 months. Images were reviewed blind to treatment allocation and clinical information. Mean ADC of peripheral (PZ) and transition (TZ) zones, and MR-suspicious lesions were compared between groups over 6 months. Conspicuity was defined as the PZ divided by tumour ADC, and its change over 6 months was assessed. Results A decrease in mean conspicuity in the dutasteride group (but not the controls) was seen over 6 months (1.54 vs 1.38; p = 0.025). Absolute changes in ADC and conspicuity were significantly different between placebo and dutasteride groups at 6 months: (-0.03 vs 0.08, p = 0.033) and (0.11 vs -0.16, p = 0.012), as were percentage changes in the same parameters: (2.27% vs 8.56% p = 0.048) and (9.25% vs -9.89% p = 0.013). Conclusions Dutasteride was associated with increased tumour ADC and reduced conspicuity. A lower threshold for triggering biopsy might be considered in men on dutasteride undergoing mpMRI for prostate cancer. Key points Dutasteride increases ADC and reduces conspicuity in small mpMRI-visible prostate cancers. Knowledge of dutasteride exposure is important in the interpretation of prostate mpMRI. A lower threshold for triggering biopsy may be appropriate on dutasteride.
Prostatic neoplasms; Diffusion Magnetic Resonance Imaging; Molecular Imaging; Dutasteride; Placebo
Prostate cancer often behaves in an indolent fashion even
without treatment, so that many men with small low-grade
tumours are suitable for active surveillance.
Dutasteride inhibits the enzyme 5 alpha-reductase that
converts testosterone to dihydrotestosterone (DHT), and is widely
used for the treatment of lower urinary tract symptoms
(LUTS) associated with an enlarged prostate . Its clinical
use for prostate cancer is not licensed but has been
investigated in four published studies.
The first was a large randomised study in 6729 men
(REDUCE) by Andriole et al. that showed that dutasteride
reduced the period prevalence of prostate cancer by 24%
compared to placebo . The second study (REDEEM)
randomised men with low risk prostate cancer on active
surveillance to daily dutasteride 0.5 mg or placebo over 3 years.
Fifty-four of 144 (38%) men in the dutasteride group were
deemed to have progressed at 3 years, compared to 70 of
145 (48%) of controls .
Two other randomised trials have investigated the use of
anti-androgen therapy in prostate cancer. The ARTS study 
showed that dutasteride significantly delayed the time to
prostate specific antigen (PSA) doubling and disease progression
(which included PSA- and non-PSA-related outcomes)
compared with placebo after 24 months of treatment (p < 0.001).
Conversely, the AVIAS trial  was a small-scale phase II
randomised controlled trial that showed no benefit to the
addition of dutasteride to an intermittent androgen deprivation
Although it is known that dutasteride is associated with a
reduction in the overall prostate volume of 25% after 3-6
months exposure, the mechanism by which prostate cancer
prevalence is reduced remains unclear .
In order to further explore the mechanisms at work we
undertook specific analyses on the diffusion-weighted
sequences that were derived from the MAPPED study – a
randomised study of dutasteride versus placebo in men with
low risk prostate cancer that used multi-parametric Magnetic
Resonance Imaging (mpMRI) as an endpoint .
Materials and methods
This study represents a planned analysis from a phase II,
randomised, double blind, prospective clinical trial approved
by the Hammersmith & Queen Charlotte’s & Chelsea
Research Ethics Committee (UK) (09/H0707/84), and the
Medicines & Health Regulatory Agency and registered on
the European Clinical Trials register (EudraCT
2009102405-18) . The study was investigator-led, and
sponsored by University College London. It was funded through
an unrestricted grant by GlaxoSmithKline (GSK). All patients
gave written informed consent to participate in this study, and
were blinded to treatment allocation.
Eligibility criteria and study design
Between June 2010 and January 2012, 42 men were recruited,
and 40 completed the study; the full study protocol has been
published . An initial routine 1.5 T mpMRI for the
assessment of prostate cancer showed at least a 0.2 cc lesion at
mpMRI (T2-weighted, diffusion-weighted imaging - DWI
or dynamic contrast enhanced - DCE -) for all men, in line
with standard guidelines . Eligible men met the UK
National Institute for Health and Clinical Excellence (NICE)
2014 active surveillance criteria .
Specifically, inclusion criteria for this retrospective analysis
were: (1) Gleason 3 + 3 or 3 + 4 prostate cancer based on
biopsy within the preceding two years (this biopsy was not
standardised and was not part of the trial); (2) PSA ≤ 15 ng/
mL; and (3) lesion scoring ≥ 4 at baseline mpMRI, according
to the dominant sequence as reported in the Prostate imaging
reporting and data system (PI-RADS) version 2 guidelines
From the initial population (n = 40) we identified three men
with a lesion scoring ≤ 3 at baseline mpMRI according to
PIRADS version 2 guidelines , and we therefore excluded
them. It is important to stress that all men included in this
study did not have any prostate cancer treatment (hormone
manipulation, prostatic surgery, and treatment with any
5alpha reductase inhibitor) in the previous 12 months.
A 3T MR scan including T1- and T2-weighted and DW
imaging was performed and, after review by a study
radiologist confirming suitability, men were individually randomised
(1:1) to placebo or dutasteride using block randomisation with
varying block sizes. MpMRI was repeated at 6 months and an
exit biopsy was offered to all men, with ten standard cores and
additional cores targeted to the MRI lesion using visual
registration  to include targeting of MR lesions. Prostate
Specific Antigen (PSA) was assessed at baseline and 6
MR imaging technique
All patients underwent MR imaging using a 3T system
(Magnetom Verio, Syngo MR B17; Siemens Healthcare,
Erlangen, Germany) and a pelvic phased-array coil. All
examinations included unenhanced axial, sagittal and coronal turbo
spin-echo T2 weighted imaging and axial DWI (b values of 0,
100, 800 and 1400 s/mm2 used for calculation of ADC map).
The parameters on the multi-b value DWI were: repetition
time 4300 msec, echo time 80 msec, acquisition matrix 126
x 81, field of view 245 mm x 213 mm, slice thickness 5 mm,
flip angle 90°, number of averages 6. A dedicated b = 1400
s/mm2 sequence was obtained using similar parameters but
with 16 averages. Dynamic gradient echo sequences were
obtained during intravenous injection of 0.1 mmol/kg of body
weight of gadoterate meglumine (Dotarem®, Guerbet, Roissy,
France) at a rate of 2 mL/s.
The protocol was in line with standard guidelines .
All MR imaging data sets were anonymised prior to
retrospective consensus review by two board-certified uro-radiologists
(AK and FG, with 10 and 3 years of experience in prostate
cancer mpMRI interpretation, respectively) using commercial
image viewing software (Osirix ® v. 4.1.2; Geneva,
Switzerland). Both readers were unaware of treatment
allocation and PSA results and were privy only to the date of the
scan. For the purposes of image interpretation, the lesion was
defined as a focal area that displayed (1) focal low signal
intensity on T2-weighted images, (2) high signal on the
DWI (b = 1400 s/mm2) and (3) focal restricted diffusion on
the ADC map and early-peaking enhancement on the dynamic
series. The individual lesions were assigned overall scores
from 1 to 5 based on the PIRADS v.2 guidelines .
Region of interest (ROI) assessment
Image quality was sufficient to evaluate ADC in all patients.
ADC values were obtained from regions of interest (ROI)
traced on ADC maps, making reference to the corresponding
DWI sequences and the other sequences (T2-weighted and
Fig. 1 The arrows show a
tumour in the right mid-apex
peripheral zone of the prostate on
diffusionweighted (b) and dynamic
contrast-enhanced (c) imaging,
and how all regions of interest
(ROIs) were positioned on the
same slice of the apparent
diffusion coefficient (ADC) map
DCE). The largest lesion (index tumour) was chosen for
analysis if multiple foci were detected in the same patient.
On the same slice, the readers also copied and pasted two
ROIs of the same size of the whole lesion ROI both in the
noncancerous peripheral (PZ) and transitional (TZ) zone - in
mirror position to the lesion (Fig. 1) - and calculated the
additional ADC values. Because the ROI of a small lesion (which is a
common situation in men on active surveillance) is likely to
include elements only partially filling the slice, we used a
modified method for the calculation of ADC of the tumour,
in order to minimise such partial volume effects. Specifically,
a smaller ROI was traced inside the whole lesion ROI, with a
diameter corresponding to half of the diameter of the greater
ROI, and the mean tumour ADC value was calculated from
this area (Fig. 2). The same ROIs were used for the
measurement of signal intensity (SI) on the dedicated long b (1400
s/mm2) DWI sequence.
We defined the term conspicuity as the mean ADC of the PZ
divided by the mean ADC of the tumour.
Fig. 2 Image from patient
reported in Fig. 1 showing our
modified method for the
calculation of tumour ADC to
minimise partial volume effects.
A smaller ROI was traced inside
the whole tumour ROI, with a
diameter (BC) corresponding to
the half of the diameter of the
greater ROI (AB). The ADC
value for the lesion was calculated
from this area
Mean and standard deviations were used to summarise
continuous variables. Categorical data were expressed by
frequencies and percentages.
To detect significant changes in DWI ADC, conspicuity and
SI between baseline and 6-month scans, paired T-tests were
carried out in the placebo and dutasteride groups. A paired t test was
also used to check for differences in the size of the ROIs used to
measure these parameters at baseline and 6 months.
To detect a difference between the mean change (either
absolute or percentage) of ADC, conspicuity and SI between
the two groups (placebo vs dutasteride) we performed
P values less than 0.05 were considered to indicate a
All statistical analyses were performed by using SPSS
(version 20.0; SPSS, Chicago, Illinois, USA).
A total of 37 men were analysed in this study (19 in the
placebo and 18 in the dutasteride arm, respectively), with a
mean age of 65 years (range 49-79). All lesions were visible
both at baseline and 6-month scans on DWI, permitting the
calculation of tumour ADC values in all men. Of note, 35/37
(95%) suspicious regions evaluated for ADC calculation on
mpMRI were concordant for the presence of cancer at entry
biopsy. Twenty-eight out of 37 (76%) lesions were also
concordant at exit biopsy, 2/37 (5%) were discordant - one in the
placebo and one in the dutasteride group - and 7/37 (19%)
men declined the exit biopsy - four in the placebo and three
in the dutasteride arm.
There were 33/37 (89%) lesions scoring 4 and 4/37 (11%)
lesions scoring 5 at baseline mpMRI, according to PI-RADS
version 2 . Two lesions in the placebo arm were
downgraded from PI-RADS 4 to PI-RADS 3 after 6 months.
Lesion locations were as follows: 33/37 (89%) in the PZ
[20/37 (54%) on the right, 12/37 (32%) on the left and 1/37
(3%) midline] and 4/37 (11%) in the TZ.
There was no difference in PSA values between the placebo
and the dutasteride group at baseline (6.12 ± 2.20 vs 7.14 ±
2.23 ng/mL, p = 0.168). There was a significant difference in
PSA values between the two arms after 6 months (6.72 ± 2.39
vs 4.14 ± 1.65 ng/mL, p = 0.001).
Nineteen out of 37 men (51%) had Gleason 3 + 3 and 18/37
(49%) Gleason 3 + 4 at entry biopsy.
Table 1 summarises the mean ROIs measurements at
baseline and 6-month scans.
Table 1 Mean ROI areas (cm2)
for each of the two arms at
baseline and after 6 months
Standard ROI (cm2)
Modified ROI (cm2)
Note - Data are means with standard deviations in parentheses. MRI: magnetic resonance imaging; ROI: region of
interest. Paired t test used for comparisons
Note - Data are means with standard deviations in parentheses. MRI: magnetic resonance imaging; ADC:
apparent diffusion coefficient (x 10-3 mm2 /s); TZ: transition zone; PZ: peripheral zone; SI: signal intensity.
Paired t test used for comparisons
Table 2 ADC, conspicuity and
signal intensity values for each of
the two arms included in the study
at baseline and after 6 months
Table 2 shows mean ADC values, conspicuity and SI from
mpMRI at baseline and at the end of the trial (6 months).
There were no significant differences over 6 months both for
men randomised to placebo or dutasteride for ADC values. A
decrease in mean conspicuity and SI over 6 months was
observed for men on dutasteride (1.54 vs 1.38; p = 0.025) and
(56.59 vs 48.99, p < 0.01), respectively.
Table 3 reports the difference in absolute values between
men taking placebo or dutasteride over 6 months. Significant
changes in absolute tumour ADC and conspicuity between the
two groups were observed (-0.03 vs 0.08, p = 0.033) and (0.11
vs –0.16, p = 0.012), respectively (Fig. 3 and Fig. 4). A
significant difference was also noted for ADC values in the TZ
(0.07 vs 0.04, p = 0.039) and signal intensity (3.75 vs –5.93,
p = 0.036), respectively.
Table 4 shows the comparison of the percentage changes
between men taking placebo or dutasteride. A significant
percentage increase in tumour ADC (8.56% vs -2.27%, p =
0.048) and a significant decrease in conspicuity (-9.89% vs
9.25%, p = 0.013) and SI (-6.95% vs 7.93%, p = 0.039) were
observed in the dutasteride group when compared to the
placebo arm (Fig. 5).
Table 3 Differences of absolute values over 6 months for ADC,
conspicuity and signal intensity for each of the two arms included in the
Note - Data are means with standard deviations in parentheses. MRI:
magnetic resonance imaging; ADC: apparent diffusion coefficient (x
10-3 mm2 /s); TZ: transition zone; PZ: peripheral zone; SI: signal
intensity. Unpaired t test used for comparison between placebo and dutasteride
In summary, men with localised prostate cancer who were
randomised to dutasteride exhibited a (1) significant decrease
in mean tumour conspicuity, (2) a significant reduction on SI
on DWI, and (3) a significant increase in tumour ADC, over a
6-month period compared to the men who were randomised to
Before considering the clinical and research implications of
our findings, it is worth reviewing some of the inevitable
methodological issues that were inherent with both the design
and conduct of this first ever study to use imaging as a primary
endpoint in a study of localised prostate cancer.
The first, and possibly most important, is that the men
entered the study largely by means of transrectal ultrasound
(TRUS) guided biopsy but exited the study by an
imageguided biopsy. As we now know (but were less aware of when
the study was conceived) these two methods of assessment
yield quite different results given a stable disease status .
Fortunately, this aspect of the trial design does not impact on
the objectives of our current analysis, which limits itself to the
Second, the cohort is relatively small and, as a result, may
not be fully representative of the spectrum of mpMRI-derived
lesions in the population. The original MAPPED study was
powered to show a 20% difference in tumour volume, and the
predetermined end points were met. Clearly, further studies
are going to be needed to improve the degree to which we
are representative of the disease that we are studying. For
instance, peripheral zone tumours were over represented in
our cohort, and, as a consequence, transition zone tumours
were less common. This might explain our observation of a
reduction in ADC within the transition zone of the
placebotreated tumours - something we did not observe in the
peripheral zone. The inherent heterogeneity of the transition zone is
likely to introduce bias and that will only be countered by
increasing the number of subjects assessed.
Finally, the method used for the measurement of ADC may
(even with the modified method used in this study) be prone to
Fig. 3 63-year-old man with a presenting PSA of 5.81 ng/mL and
Gleason Score 3 + 4. At baseline MRI, the pathological area of
decreased signal intensity in the mid-right peripheral (arrow) on the
axial T2-weighted image (A) corresponds to the high-signal intensity on
the DWI image (B) and low-signal intensity on the ADC map (C), with a
reduced ADC value (0.88 x 10-3 mm2/s). At 6-month MRI (PSA: 2.41 ng/
mL) the pathological area is less recognisable (arrow) in all the three
scans (D,E,F) and an increase in the ADC value was observed (1.01 x
10-3 mm2/s). There was a decrease in conspicuity of 11% on the ADC
map. This patient was in the dutasteride arm
some edge effects and this is a problem that will affect any
study using parametric assessment of small prostate lesions:
the possibility that changes in lesion size will change apparent
quantitative measurements because of edge effects must
always be borne in mind.
Despite these methodological issues, we feel that our
findings are important both clinically and in terms of our future
understanding of prostate cancer progression.
From a clinical perspective our results show that men
on dutasteride may be less likely to have their cancer
called: reduced ADC (both absolute and relative to
surroundings) and high signal on long b images are the key
elements of tumour detection using DWI in PIRADS 2
. In response, as a minimal standard, radiologists
should be made aware of the dutasteride or finasteride
exposure to help them interpret the finding on mpMRI.
Fig. 4 67-year-old man with a presenting PSA of 6.64 ng/mL and
Gleason Score 3 + 3. At baseline MRI, the pathological area of
decreased signal intensity in the anterior part of the transition zone
(arrow) on the axial T2-weighted image (A) corresponds to the
highsignal intensity on the DWI image (B) and low-signal intensity on the
ADC map (C), with a reduced ADC value (0.87 x 10-3 mm2/s). At
6month MRI (PSA: 8.10 ng/mL) the pathological area is still recognisable
(arrow) in all the three scans (D,E,F) and a decrease in the mean ADC
value was observed (0.63 x 10-3 mm2/s). There was an increase in
conspicuity of 36% on the ADC map. This patient was in the placebo arm
Table 4 Differences for ADC, conspicuity and signal intensity change
over 6 months (expressed as percentage) for each of the two arms
included in the study
Note - Data are means with standard deviations in parentheses. Δ: change
(%); ADC: apparent diffusion coefficient; SI: signal intensity. Unpaired t
test used for comparison between placebo and dutasteride groups
For the future, the architects of PIRADS III or IV may
wish to make specific recommendations for men exposed
to these agents.
As the exposure to antiandrogen therapy seems to reduce
tumour conspicuity when mpMRI are performed to assess for
prostate cancer, our findings support the idea that a lower
threshold for triggering biopsy might be considered in men
taking dutasteride or finasteride. In active surveillance it is
possible that these drugs may increase the proportion of small,
low grade tumours that are seen poorly or not at all, a factor
which might be taken into account in follow-up protocols.
From a research perspective our results are of considerable
interest in that they point to a potentially valid, largely reliable
and responsive imaging biomarker that may be providing
noninvasive information on tumour status. In 2009, Padhani et al.
alerted us to the importance (and potential utility) of assessing
the effect of a drug (in absolute terms and in direction) on
ADC values . Our data provides a preliminary response
to this challenge.
Nevertheless, the question, ‘What biological processes is
mpMRI revealing to us?’ remains both important and pertinent.
We know from radical prostatectomy studies that were
conducted after short-term dutasteride exposure that cellular
involution and epithelial shrinkage occurs in benign tissue in addition to
the increase in the stromal/epithelial ratio in prostate cancer,
suggesting that dutasteride may induce significant phenotypic
alterations in both the benign and the neoplastic prostate . It is
possible therefore that the increase in ADC that we are observing
in dutasteride-treated prostate cancer may be due to a change in
the cellular components of the cancer.
The ADC increase that we observed in the dutasteride arm of
the study is certainly consistent with previous evidence; an
increase in ADC values has been associated when a cytotoxic
selective pressure was applied . In addition, antiandrogen
treatments (dutasteride being a weaker bedfellow) have been shown to
reduce prostatic blood flow, causing nuclear shrinkage, cell
vacuolisation, apoptosis and necrosis in prostate cancer ,
resulting in an increase in the ADC values. There is some
suggestion that these ADC values, whatever it is they are telling us
about tumour status, may have some clinical relevance. De Souza
et al.  previously showed that the ADC of high or intermediate
risk prostate cancer is lower than that of low-risk tumours and
suggested that in patients with low-risk, localised disease, tumour
ADC may be a useful marker of progression .
In conclusion, our results show that dutasteride is associated
with an increase in tumour ADC and reduces tumour
conspicuity on DWI. This may adversely impact on cancer detection
rates in men exposed to 5-alpha reductase inhibitors. As a
minimum, radiologists should be made aware of the treatment
status of the prostate.
Fig. 5 Ladder plots showing tumour ADC (A) and conspicuity (B)
changes over 6 months for each of the two arms included in the study.
The error bars at 6 months confirm a significant increase in ADC and
decrease in conspicuity in men treated with dutasteride (red, dashed line)
when compared to men in the placebo arm (blue, continuous line)
Acknowledgements The authors are indebted to all the men who
greatly contributed to the realisation of this study.
Compliance with ethical standards
Conflict of interest The authors of this manuscript declare
relationships with the following companies:
Mark Emberton is a UK National Institute of Health Research (NIHR)
Senior Investigator. In addition, he receives research support from the
UCLH/UCL NIHR Biomedical Research Centre.
Ramiro Castro, MD, is a full GSK R&D employee.
Alex Kirkham receives research support from the UCLH/UCL NIHR
Biomedical Research Centre.
Funding The study was investigator-led and sponsored by University
The study was supported financially by GSK who also provided
supplies of both drug and placebo. GSK had no input into the design, conduct
and analysis of the study. The manuscript has been reviewed by GSK but
final editorial control rests with the principal investigator (Mark
Emberton), who serves as guarantor of the study.
Statistics and biometry
sary for this paper.
No complex statistical methods were
necesInformed consent Written informed consent was obtained from all
subjects (patients) in this study.
Ethical approval Institutional Review Board approval was obtained.
Study subjects or cohorts overlap Some study subjects or cohorts
have been previously reported in:
Moore CM, Robertson NL, Jichi F, et al (2017) The effect of dutasteride
on MRI-defined prostate cancer lesions: MAPPED (Magnetic resonance
imaging in Primary Prostate Cancer after Exposure to Dutasteride) – a
randomized placebo-controlled, double-blind clinical trial. J Urol.
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