Francesco Giganti

Giulio Gambarota

Caroline M Moore

Nicola L Robertson

Neil Mccartan

Charles Jameson

Simon R J Bott

Mathias Winkler

Brandon Whitcher

Ramiro Castro-Santamaria

Prostate cancer detection using quantitative T and T -weighted imaging The effects of 5-alpha-reductase inhibitors in men on active surveillance

Keywords: Prostatic neoplasms, Active surveillance, Magnetic Resonance Imaging, Quantitative T2, Dutasteride, Placebo

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INTRODUCTION

Multiparametric magnetic resonance imaging (mpMRI) combines high-resolution T2weighted imaging (T2-WI) sequences with dynamic contrast-enhanced -DCE -and diffusion-weighted imaging -DWI -, and/or spectroscopy [START_REF] Petrillo | Multiparametric MRI for prostate cancer detection: performance in patients with prostate-specific antigen values between 2.5 and 10 ng/mL[END_REF]. Today mpMRI plays a pivotal role in the diagnosis and risk stratification of men with prostate cancer [START_REF] Penzkofer | Prostate cancer detection and diagnosis: the role of MR and its comparison with other diagnostic modalities--a radiologist's perspective[END_REF]. The key sequences that drive this process are T2-WI and DWI with DCE providing useful input in select cases [START_REF] Nowak | The value of ADC, T2 signal intensity, and a combination of both parameters to assess Gleason score and primary Gleason grades in patients with known prostate cancer[END_REF][START_REF] Marcus | The impact of multiparametric pelvic magnetic resonance imaging on risk stratification in patients with localized prostate cancer[END_REF].

T2-WI generates a high signal-to-noise ratio and confers high spatial resolution. These attributes permit the depiction of subglandular structures and for the differentiation of the zonal anatomy of the prostate (e.g. peripheral/transitional zone, seminal vesicles, neurovascular bundles and urethra) [START_REF] Choi | Functional MR imaging of prostate cancer[END_REF][START_REF] Hoeks | Prostate cancer: multiparametric MR imaging for detection, localization, and staging[END_REF].

The peripheral zone is characterized by high signal intensity on T2-WI, due to its higher water content, and cancer is frequently seen as an area of lower signal intensity.

However, other conditions such as prostatitis, fibrosis, scar tissue, post-biopsy hemorrhage may also cause low T2 signal intensity, and result in false positive diagnoses [START_REF] Panebianco | Pitfalls in Interpreting mp-MRI of the Prostate: A Pictorial Review with Pathologic Correlation[END_REF]. The degree of intensity decrease on T2-WI in the peripheral zone has been correlated with Gleason score, with higher Gleason scores having lower signal intensities [START_REF] Wang | Assessment of biologic aggressiveness of prostate cancer: correlation of MR signal intensity with Gleason grade after radical prostatectomy[END_REF]. T2-WI is also considered the most important sequence for the detection of cancer in the transitional zone according to recent guidelines [START_REF] Weinreb | PI-RADS Prostate Imaging -Reporting and Data System: 2015, Version 2[END_REF][START_REF] Hoeks | Transition zone prostate cancer: detection and localization with 3-T multiparametric MR imaging[END_REF], even though the heterogeneous appearance of benign prostate hyperplasia nodules in the transitional zone makes assessment for cancer challenging in this area [START_REF] Rosenkrantz | Comparison of interreader reproducibility of the prostate imaging reporting and data system and likert scales for evaluation of multiparametric prostate MRI[END_REF].

Historically, T2-WI information has been used by radiologists in a qualitative manner and imputed into risk models such as Prostate Imaging Reporting and Data System (PI-RADS) [START_REF] Weinreb | PI-RADS Prostate Imaging -Reporting and Data System: 2015, Version 2[END_REF]. However, quantitative derivatives (T2 relaxation time) can also be generated from the T2-WI. These outputs may be useful in helping to discriminate clinically significant cancer from the background signal.

Roebuck and colleagues evaluated T2 values on a pixel-by-pixel base using Carr-Purcell-Meiboom-Gill (CPMG) quantitative imaging, and found that prostate cancer shows a significantly shorter T2 value when compared to healthy tissue [START_REF] Roebuck | Carr-Purcell-Meiboom-Gill imaging of prostate cancer: quantitative T2 values for cancer discrimination[END_REF].

It is known that dutasteride inhibits the enzyme 5 alpha-reductase, which converts testosterone to dihydrotestosterone, and is widely used for the treatment of lower urinary tract symptoms associated with an enlarged prostate [START_REF] Roehrborn | Efficacy and safety of a dual inhibitor of 5-alpha-reductase types 1 and 2 (dutasteride) in men with benign prostatic hyperplasia[END_REF]. Dutasteride is associated with a reduction of prostate volume, and there is evidence that dutasteride may delay the rate of progression in men on active surveillance for prostate cancer [START_REF] Fleshner | Dutasteride in localised prostate cancer management: the REDEEM randomised, double blind, placebo-controlled trial[END_REF].

However, it is not known what effect dutasteride may have on the appearance of prostate cancer on T2-WI, and this is a clinically important information since mpMRI is gaining popularity as one of the assessment tools in patients on active surveillance.

In order to further evaluate the role of quantitative T2 outputs we undertook specific analyses on the T2-WI and multi-echo CPMG sequences from men recruited into MAPPED -a randomized study of dutasteride versus placebo in men with low risk prostate cancer on active surveillance, using mpMRI as an endpoint [START_REF] Robertson | MAPPED study design: A 6month randomised controlled study to evaluate the effect of dutasteride on prostate cancer volume using magnetic resonance imaging[END_REF].

Our aim was to measure the T2 relaxation time, a biomarker of tissue pathology, in cancerous and non-cancerous tissue, and to examine the effect of dutasteride on those parameters.

MATERIALS AND METHODS

This study is a retrospective analysis from a phase Quantitative T2 imaging was performed with a multi-echo approach based on the CPMG imaging sequence [START_REF] Roebuck | Carr-Purcell-Meiboom-Gill imaging of prostate cancer: quantitative T2 values for cancer discrimination[END_REF]. The vendor-supplied CPMG sequence consisted of optimized 180° sinc refocusing pulses, with spoiler gradients of constant amplitude applied around each refocusing pulse along the frequency-encoding direction [START_REF] Gambarota | NMR properties of human median nerve at 3 T: proton density, T1, T2, and magnetization transfer[END_REF]. The multi-echo CPMG protocol was optimized to ensure a good compromise between several parameters; these included the in-plane spatial resolution, the sampling of the T2 relaxation decay, the signal-to-noise ratio and the scan time. Protocol optimization was carried out on 3 healthy volunteers; the CPMG sequence parameters chosen for the quantitative T2 imaging of the current study are shown in Table 1.

Image analysis

All mpMRI data were anonymized. Two board-certified radiologists (AK and FG, with 11 and 4 years of experience in prostate cancer mpMRI interpretation, respectively) reviewed the scans in consensus according to PI-RADS v.2 guidelines (9), using commercial image viewing software (Osirix ® v. 4.1.2; Geneva, Switzerland). Both readers were unaware of treatment allocation and were privy only to the date of the scan. To ensure consistency, all scans were reported in chronological order (i.e. first baseline, and then 6-month scan).

All lesions were visible on T2-WI (used as the reference standard) at baseline and after 6 months, and image quality was adequate in all patients.

First, the two readers manually traced three regions of interest (ROIs) on the T2weighted high-resolution images. The largest lesion (index tumor) was chosen, if multiple foci were detected in the same patient. The ROI was copied and pasted in the noncancerous peripheral (PZ) and transitional (TZ) zone, in mirror position to the lesion (Fig. 1) on the same slice. The signal values from this sequence were defined as T2-weighted (T2W).

The three ROIs were then copied and pasted on the multi-echo CPMG sequence.

Quantitative T2 data analysis of each ROI started with visual inspection of the T2 relaxation decays. The signal of the first echo was observed to be lower than expectedat times even lower than the second echo. This is in line with previous observations on CPMG data [START_REF] Roebuck | Carr-Purcell-Meiboom-Gill imaging of prostate cancer: quantitative T2 values for cancer discrimination[END_REF][START_REF] Gambarota | Osmotic effects on the T2 relaxation decay of in vivo muscle[END_REF]. Thus, the signal of the first echo was omitted from the data analysis. T2 values were estimated by fitting the signal 𝑆𝑆 𝑛𝑛 obtained at the echo times

𝑇𝑇𝑇𝑇 𝑛𝑛 (n = 2, 3, …, 8) to the mono-exponential decay function 𝑆𝑆 𝑛𝑛 = 𝑆𝑆 0 𝑒𝑒 -𝑇𝑇𝑇𝑇 𝑛𝑛 𝑇𝑇2
� where 𝑆𝑆 0 is a parameter proportional to the tissue proton density and external experimental factors.

T2 data fitting was performed using MATLAB (MathWorks, Natick, MA, USA). The T2 values of the lesion, PZ and TZ were determined both at baseline and after 6 months.

For each patient, we also measured the signal intensity of the lesion (𝑆𝑆 𝐿𝐿 ) and compared it to the signal intensity of presumed non-cancer tissue in mirror position, i.e. (𝑆𝑆 𝑃𝑃𝑃𝑃 ) for (𝑆𝑆 𝐿𝐿 ) in the PZ and (𝑆𝑆 𝑇𝑇𝑃𝑃 ) for (𝑆𝑆 𝐿𝐿 ) in the TZ on T2-WI. For example, we calculated the T2W contrast between a lesion in the PZ and the non-cancerous tissue using the equation:

T2W contrast = (S 𝑃𝑃𝑃𝑃 -𝑆𝑆 𝐿𝐿 )/S 𝑃𝑃𝑃𝑃 . Furthermore, to investigate whether there was a correlation between the T2-weighted and the quantitative T2 imaging data, we calculated a 'synthetic' contrast using the T2 values obtained from the CPMG data fitting. The calculation was as follows: first, we calculated the signal intensity that the lesion (with a T2 obtained from quantitative T2 imaging) would yield in the T2-weighted image. This was achieved by using the equation S 𝐿𝐿 𝑠𝑠 = 𝑆𝑆 0 𝑒𝑒 between T2 values of lesions and non-cancerous tissues (for PZ and TZ) at baseline and after 6 months. There was a significant difference (p < 0.001) between lesions and PZ for each arm, both at baseline and after 6 months (Fig. 2). Table 4 reports the comparison for T2 values from all ROIs for each of the two arms, at baseline and after 6 months.

There were no significant differences both for lesions and non-cancerous tissues (PZ and TZ). It should be noted that the median values in the PZ for the placebo arm at baseline were virtually the same as those after 6 months. The same finding was observed in the dutasteride arm.

No significant differences for T2W contrast at baseline and after 6 months were observed, both in the placebo [0.40 (0.29-0.49) vs 0.43 (0.25-0.49); p=0.881] and dutasteride arm [0.35 (0.24-0.47) vs 0.37 (0.22-0.44); p = 0.668] (Fig. 3). Additionally, there were no significant differences in T2W contrast between the placebo and the dutasteride arm at baseline [0.40 (0.29-0.49) vs 0.35 (0.24-0.47); p = 0.409] and after 6 months [0.43 (0.25-0.49) vs 0.37 (0.22-0.44); p=0.372].

There was a significant, positive correlation between T2W and T2Q contrast values (r=0.786; p < 0.001), as shown in Fig. 4.

DISCUSSION

Our previous paper [START_REF] Moore | The Effect of Dutasteride on Magnetic Resonance Imaging Defined Prostate Cancer: MAPPED-A Randomized, Placebo Controlled, Double-Blind Clinical Trial[END_REF] showed a reduction in tumor volume on T2-WI in men on dutasteride for 6 months compared to men on placebo. A further paper analyzing the DWI ( 21) has shown a reduction in conspicuity of prostate cancer in men on dutasteride for 6 months compared to placebo.

In this paper, we report the analysis of dedicated research sequences, namely quantitative T2 imaging, at the same time as the anatomical T2-WI, but not previously analyzed. In contrast to the effect on DWI, the T2Q contrast values (quantitative) and the T2W contrast (qualitative) appear to be unaffected by exposure to dutasteride.

Quantitative T2 imaging allows for measuring the T2 relaxation time, a biomarker sensitive to tissue microenvironment. However, during a standard mpMRI of the prostate, only qualitative T2 imaging (with a high signal-to-noise ratio and spatial resolution) is performed, to differentiate the zonal anatomy of the gland and the possible presence of cancer [START_REF] Weinreb | PI-RADS Prostate Imaging -Reporting and Data System: 2015, Version 2[END_REF]. Cancerous tissue consists of highly compacted cells, and this results in a decrease in T2 signal [START_REF] Dregely | Rapid quantitative T2 mapping of the prostate using three-dimensional dual echo steady state MRI at 3T[END_REF].

Although several recent studies have also evaluated the utility of quantitative T2 imaging in prostate cancer [START_REF] Roebuck | Carr-Purcell-Meiboom-Gill imaging of prostate cancer: quantitative T2 values for cancer discrimination[END_REF][START_REF] Foltz | Changes in apparent diffusion coefficient and T2 relaxation during radiotherapy for prostate cancer[END_REF][START_REF] Yu | Development of a Combined MR Fingerprinting and Diffusion Examination for Prostate Cancer[END_REF][START_REF] Skorpil | Motion corrected DWI with integrated T2-mapping for simultaneous estimation of ADC, T2-relaxation and perfusion in prostate cancer[END_REF][START_REF] Yamauchi | Prostate cancer discrimination in the peripheral zone with a reduced field-of-view T(2)-mapping MRI sequence[END_REF][START_REF] Dregely | Rapid quantitative T2 mapping of the prostate using three-dimensional dual echo steady state MRI at 3T[END_REF][START_REF] Simpkin | Relationship between T2 relaxation and apparent diffusion coefficient in malignant and non-malignant prostate regions and the effect of peripheral zone fractional volume[END_REF][START_REF] Starobinets | Improved multiparametric MRI discrimination between low-risk prostate cancer and benign tissues in a small cohort of 5α-reductase inhibitor treated individuals as compared with an untreated cohort[END_REF], quantitative in vivo T2 mapping is still a challenge due to the long scan duration, and therefore this approach is not routinely performed during a standard prostate mpMRI scan.

Our retrospective study aimed to fill this gap by analyzing a cohort of men on active surveillance exposed to dutasteride as part of the initial trial, who underwent a dedicated multi-echo T2 sequence in addition to the standard mpMRI [START_REF] Robertson | MAPPED study design: A 6month randomised controlled study to evaluate the effect of dutasteride on prostate cancer volume using magnetic resonance imaging[END_REF]. The data acquisition protocol was optimized to yield the full volume coverage of the prostate, a good in-plane spatial resolution and a detailed sampling of the T2 relaxation decay in order to obtain an accurate measurement of the T2 relaxation time. The data analysis was performed on the ROIs, and data fitting was carried out offline with MATLAB.

It is known that antiandrogen therapy affects prostatic tissues, which inevitably affects the interpretation of mpMRI studies. The quantitative T2 values are closely related to tissue properties and in our study, they were not influenced by dutasteride.

The correlation between the T2W and T2Q contrast provides insight into the results obtained from the qualitative and quantitative T2 imaging data. Considerable variability of the contrast in the T2-WI was observed; same consideration applies to quantitative T2 measurements, where different T2 values were measured in different patients. Does this variability in T2-WI contrast and quantitative T2 values originate from measurement error, or reflect true inter-individual differences? The correlation found between the contrast measured on the T2-weighted images and the "synthetic" contrast calculated from the quantitative T2 measurement indicates that the variability could be partly explained by inter-individual differences. In other words, in patients with a high lesion contrast in the PZ (measured on T2-WI), the T2 values measured by T2Q would have yielded T2-weighted images with a high contrast. Similarly, in patients with a low lesion contrast in the PZ, the T2 values would have yielded T2-weighted images with a low contrast.

Starobinets and colleagues [START_REF] Starobinets | Improved multiparametric MRI discrimination between low-risk prostate cancer and benign tissues in a small cohort of 5α-reductase inhibitor treated individuals as compared with an untreated cohort[END_REF] reported no significant differences in contrast on T2-WI between untreated and treated men. Similarly, we did not find any difference between the two arms, both at baseline and after 6 months of exposure to dutasteride. Following our definition of contrast, we could consider this parameter as a surrogate of the conspicuity of the lesion on T2-WI. It follows that the use of dutasteride does not seem to influence lesion conspicuity on T2-WI (i.e. the lesion is still detectable after treatment). This finding is also supported by the significant difference in T2 values from quantitative T2 measurements between the lesion and non-cancerous PZ for each arm, before and after treatment.

It is known that visible lesions on mpMRI have an increased overall risk of cancer progression, so that identifying these lesions is of clinical importance [START_REF] Park | Role of multiparametric 3.0 Tesla magnetic resonance imaging in patients with prostate cancer eligible for active surveillance[END_REF].

Our results confirm that mpMRI can be used for reassessment during active surveillance in patients treated with 5-alpha-reductase inhibitors, as these medications do not affect signal intensity on quantitative and qualitative T2 imaging, although our previous publication [START_REF] Moore | The Effect of Dutasteride on Magnetic Resonance Imaging Defined Prostate Cancer: MAPPED-A Randomized, Placebo Controlled, Double-Blind Clinical Trial[END_REF] A number of methodological limitations in our study should be mentioned. First amongst these is the relatively small cohort of men. In mitigation, the men were all included in a prospective randomized controlled trial and therefore we subject to standardized mpMRI and assessment. The study was of relatively short duration for a prostate cancer study and therefore does not reflect the natural history of the condition. Secondly, some may regard the absence of tissue verification by means of radical prostatectomy step section pathological processing as a limitation. In this relatively low risk population who had elected to enroll in an active surveillance study few would choose to have surgery and therefore we would have to deal with missing data. The use of targeted biopsy -the reference test used in this study that could be applied to all men -has been shown to be as accurate as 5mm template biopsy [START_REF] Kasivisvanathan | Transperineal magnetic resonance image targeted prostate biopsy versus transperineal template prostate biopsy in the detection of clinically significant prostate cancer[END_REF]. It is acknowledged that PZ and TZ tumors are scored differently according to PI-RADS v. 2 guidelines (9), and our cohort was composed of 35 PZ and 5 TZ tumors. There is some likelihood that dissimilar evaluations would have arisen if the number of TZ lesions (more heterogeneous from a histological point of view) had been higher.

In conclusion, after this retrospective analysis, we found that T2 relaxation times and T2-WI were not significantly influenced by the exposure to dutasteride in men on active surveillance for prostate cancer. This suggests that the drug may not impair our ability to measure tumor volume in active surveillance and longitudinal studies. for quantitative T2 analysis is here illustrated. Three ROIs non-cancerous peripheral and transitional zones) were drawn on the high-resolution T2 image. These ROIs were then copied and pasted on the multi-echo images.

Figure 1

 1 Figure 1 MR images of the prostate of a 69-year-old man with a PSA of 5.83 ng/ml and a Gleason 3+4 tumor in the mid-right peripheral zone at entry biopsy. The region of interest (ROI)

Figure 2 Figure 3

 23 Figure 2 Box and whisker plots showing T2 values the three ROIs for each arm, both at baseline and after 6 months. [Bottom of box = 25 th percentile, center line = median, top of box = 75 th percentile, whiskers = 10 th and 90 th percentiles, ° = outliers (between 1.5 and 3 interquartile ranges), * = extreme outliers (more than 3 three interquartile ranges)]. PZ: peripheral zone; TZ: transition zone

  II, randomized, 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 2009-102405-
	18) (15). The study was sponsored by University College London and GlaxoSmithKline
	(GSK) funded it through an unrestricted grant.
	Eligibility criteria and study design
	All men gave their consent to participate in this study and the full protocol has been
	published (15). Between June 2010 and January 2012, 42 men were recruited, and 40
	completed the study. Eligible men had biopsy-proven low-intermediate risk prostate
	cancer and an MR visible lesion ≥ 0.2ml on T2-weighted sequences, based on biopsy
	within the preceding two years. All eligible men met the National Institute for Health and
	Clinical Excellence (NICE 2008) active surveillance criteria for low-intermediate risk
	prostate cancer (up to Gleason 3+4, PSA up to 20 ng/ml and/or clinical stage up to T2c)
	(16).
	All men included in this study did not have any prostate cancer treatment (hormone
	manipulation, prostatic surgery, and treatment with any 5-alpha 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 randomized (1:1) to daily placebo or dutasteride using block randomization
	with varying block sizes. MpMRI was repeated at 6 months.
	MR imaging
	All patients underwent MR imaging on a 3T system (Magnetom Verio, Syngo MR B 17;
	Siemens Healthcare, Erlangen, Germany) and a pelvic phased-array coil. All
	examinations included unenhanced axial, sagittal and coronal turbo spin-echo T2
	weighted imaging, axial DWI (b values of 0, 100, 800 and 1400 s/mm 2 ) with
	reconstruction of the apparent diffusion coefficient (ADC) map and axial T1-weighted
	imaging 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 (17).

  RESULTSAtotal of 40 men (median age 65.15 years; range 49-79 years) were eligible for the present study. Lesion locations were as follows: 35/40 (87 %) in the PZ [14/35 (40 %) left, 1/35 (3 %) midline and 20/35 (57 %) right] and 5/40 (13 %) in the TZ.

	-𝑇𝑇𝑇𝑇 � , where TE is the echo time (103 𝑇𝑇2
	milliseconds) of the T2W image and All men had a positive biopsy at entry; specifically, 22/40 (55%) men had Gleason score s stands for synthetic. We performed the same 3+3 and 18/40 (45%) had Gleason 3+4. Of note, thirty-seven men of forty men (93%)
	calculation for the signal of the PZ, 𝑆𝑆 𝑃𝑃𝑃𝑃 𝑠𝑠 . The last step consisted in calculating the had histological confirmation of the mpMRI lesion contained cancer either at baseline or
	'synthetic' contrast, T2Q contrast = 𝑆𝑆 𝑃𝑃𝑃𝑃 𝑠𝑠 -S 𝐿𝐿 𝑠𝑠 )/S 𝑃𝑃𝑃𝑃 𝑠𝑠 , which was obtained by using the exit. Three men had discordant histology at baseline, one of whom had a negative exit
	quantitative T2 data. biopsy (placebo group) and two who declined the exit biopsy (one placebo, one
	dutasteride).
	Statistical methods There was no difference in PSA values between the placebo and the dutasteride group at
	Clinical and demographic data are reported using descriptive statistics. Continuous baseline [6.2 (5.3-7.8) vs 6.4 (5.1-8.8) ng/mL, p = 0.482], respectively. There was a
	variables were summarized by their median values and interquartile range (IQR, 1 st significant difference in PSA values between the two arms after 6 months [6.6 (5.6-8) vs
	quartile to 3 rd quartile); categorical variables were summarized by means of frequencies 3.9 (2.2-5.6) ng/mL, p < 0.001].
	and percentages.

We carried out the Wilcoxon signed-rank test to compare baseline and 6-month values (T2 values and contrast), first in the placebo and then in the dutasteride group. The Mann-Whitney U test was applied to investigate the differences between the two groups (placebo vs dutasteride). The relationship between T2W and T2Q contrast was assessed by means of the Spearman's correlation coefficient. P values less than 0.05 were considered to indicate a significant difference. All statistical analyses were performed by using SPSS (version 20.0; SPSS, Chicago, Illinois, USA).

Table

2

compares median ROI measurements at baseline and after 6 months. There was a significant difference between baseline and 6-month ROI areas in the dutasteride arm [0.38 (0.27-0.61) vs 0.27 (0.20-0.53) cm 2 ; p = 0.005]. Table

3

reports the comparison

  suggests that 5-alpha-reductase inhibitors do result in a decrease in MRI-visible tumor volume. We agree with the PRECISE (Prostate Cancer Radiological

	Estimation of Change in Sequential Evaluation) recommendations (31) for reporting MRI
	in active surveillance that further studies are necessary to investigate exactly which
	imaging parameters (e.g. tumor volume measurements on T2-WI) would be most
	appropriate to initiate repeat biopsy or indeed treatment.

Table 1 .

 1 MRI parameters of the Carr-Purcell-Meiboom-Gill (CPMG) sequence for

	quantitative T2 imaging.

Table 2 .

 2 ROI areas (cm 2 ) for each of the two arms at baseline and after 6 months.Note -Data are medians with interquartile ranges in parentheses. ROI: region of interest.

	Placebo

Table 3 .

 3 T2 values (in milliseconds) for lesions (L) and non-cancerous tissues (PZ and TZ) at baseline and after 6 months for each of the two arms. The p-values (Wilcoxon signed-rank test) for T2 comparison between L-PZ and L-TZ are also displayed. Data are medians with interquartile ranges in parentheses PZ: peripheral zone; TZ: transition zone.

	Placebo

Table 4 .

 4 T2 values (in milliseconds) for each of the two arms included in the study at baseline and after 6 months. The p-values (Wilcoxon signed-rank test) for T2 comparison between baseline and 6-month mpMRI are also displayed.Note -Data are medians with interquartile ranges in parentheses. PZ: peripheral zone; TZ: transition zone

			Placebo			Dutasteride
		Baseline	6 months	p	Baseline	6 months	p
	Lesion	83.5 (70.1-95.8)	81.5 (72.4-100.5)	0.179	80.5 (74.2-89.5)	81.9 (72.4-85.8)	0.681
	Non-cancerous PZ	133.7 (99.6-152.4)	133.7 (109.5-157.2)	0.654	107.2 (97.1-126.6)	107.9 (95.9-129.5)	0.794
	Non-cancerous TZ	97.7 (84.4-106.0)	96.2 (88.4-103.6)	0.332	88.1 (75.4-94.6)	83.2 (76.5-90.2)	0.502

Figure 4

Scatter plot of contrast from high-resolution T2-weighted (T2W) and quantitative T2 (T2Q) imaging, showing a positive correlation (r=0.786; p < 0.001).