MRI Fusion-Targeted Transrectal Prostate Biopsy and the Role of Prostate-Specific Antigen Density and Prostate Health Index for the Detection of Clinically Significant Prostate Cancer in Southeast Asian Men

Abstract

Objective:

To test the hypothesis that targeted biopsy has a higher detection rate for clinically significant prostate cancer (csPCa) than systematic biopsy. We defined csPCa as any Gleason sum ≥7 cancer. In patients with Prostate Imaging Reporting and Data System (PI-RADS) 3 lesions, to determine if factors, such as prostate-specific antigen density (PSAD) and prostate health index (PHI), can predict csPCa and help select patients for biopsy.

Materials and Methods:

We report the first series of targeted biopsies in Southeast Asian men, with comparison against systematic biopsy. Consecutive patients were registered into a prospective institutional review board-approved database in our institution. We reviewed patients who underwent biopsy from May 2016 to June 2017. Inclusion criteria for our study were patients with at least one PI-RADS ≥3, and who underwent both targeted and systematic biopsies in the same sitting.

Results:

There were 115 patients in the study, of whom 74 (64.3%) had a previous negative systematic biopsy. Targeted biopsies detected significantly less Gleason 6 cancers than systematic biopsies (p < 0.01), and demonstrated significantly higher sensitivity, specificity, positive predictive value, and negative predictive value (NPV) for the detection of csPCa. For patients with PI-RADS 3 lesions, PHI and PSAD were found to be the best predictors for csPCa. PSAD <0.10 ng/mL/mL had an NPV of 93% and sensitivity of 92%, while allowing 20% of patients to avoid biopsy. PHI cutoff of <27 would allow 34% of patients to avoid biopsy, with both sensitivity and NPV of 100%.

Conclusions:

Targeted prostate biopsies were found to be significantly superior to systematic biopsies for the detection of csPCa, while detecting less Gleason 6 cancer. Usage of PSAD and PHI cutoff levels in patients with PI-RADS 3 lesions may enable a number of patients to avoid unnecessary biopsy.

Introduction

Although serum prostate-specific antigen (PSA) screening is not routinely performed in Singapore, the incidence of prostate cancer (PCa) is steadily increasing and ranks among the highest in Asia,¹ with an age-standardized incidence rate (ASR) of 28.6 per 100,000 person-years during 2010–2014.² In comparison, the incidence of PCa is highest in Australia/New Zealand and North America (ASR of 111.6 and 97.2 per 100,000, respectively).¹

Unlike most other solid tumors wherein biopsy is performed under image guidance or under direct observation, PCa has traditionally been detected by randomly sampling the entire gland through a systematic 10–12 core transrectal ultrasound (TRUS)-guided prostate biopsy.³ However, the introduction of multiparametric MRI (mpMRI) approximately a decade ago now allows for image-based identification of PCa, which may improve the diagnostic accuracy for clinically significant PCa (csPCa).^4
–6 In addition, the PROMIS trial data published by Ahmed et al.⁷ promoted further interest in mpMRI as a triage test for men with raised serum PSA, with higher sensitivity than TRUS biopsy for the detection of csPCa, thus allowing up to 27% of patients to avoid a primary biopsy.

To improve the diagnostic quality of mpMRI prostate and to standardize radiology reports, the European Society of Urogenital Radiology introduced in 2012 the first version of the Prostate Imaging Reporting and Data System (PI-RADS v1).⁸ More recently in 2015, a revised version (PI-RADS v2) was introduced.⁹ Based on the imaging characteristics of a lesion on the different MRI parameters, an overall score between 1 and 5 is given to a lesion to predict its chance of harboring csPCa [defined in PI-RADS v2 as cancer with Gleason sum ≥7, and/or volume ≥0.5 cc, and/or extraprostatic extension (EPE)]. For example, a PI-RADS 3 lesion has an intermediate probability of harboring csPCa, a PI-RADS 4 lesion has a high probability of harboring csPCa, and a PI-RADS 5 lesion has a very high probability of harboring csPCa.

After a PI-RADS score is assigned to a lesion, the lesion can be biopsied in a targeted way to confirm the diagnosis. There are three ways to perform targeted biopsies: (1) direct “in-bore” MRI biopsies, (2) cognitive fusion, and (3) MRI-TRUS fusion through software-based image coregistration without requiring real-time MRI scanning.¹⁰

With the increased utilization of targeted prostate biopsies, it was timely that the American Urological Association and the Society of Abdominal Radiology released in 2016 a consensus statement recommending mpMRI evaluation of patients with previous negative prostate biopsies and for targeted biopsies for patients with PI-RADS 3 to 5 lesions.¹¹ However, the same statement also mentioned that a number of studies have showed that a proportion of csPCa can be missed by MRI-targeted biopsies and thus systematic prostatic biopsies should still be performed. The European Association of Urology guidelines also recommend mpMRI evaluation before repeat prostate biopsies, and to include both targeted and systematic biopsies during repeat biopsies.³ Based on the mentioned consensus statement and guideline recommendations, we included patients with PI-RADS 3 to 5 lesions in our study.

We report the first series of transrectal-targeted prostate biopsies in Southeast Asian men utilizing the UroNav™ MRI-TRUS fusion system (Invivo, Philips Healthcare), with comparison against systematic 12-core TRUS biopsy. The main objective of the study was to test the hypothesis that targeted biopsy has a higher detection rate for csPCa than systematic prostate biopsy. We defined csPCa as any Gleason sum ≥7 cancer, which is similar to the PI-RADS v2 definition previously stated.

In addition, owing to the relatively low rates of csPCa detection for PI-RADS 3 lesions in a number of studies,^6,12,13 we analyzed whether usage of factors, such as PSA, PSA density (PSAD), prostate health index (PHI), prostate volume, location of the index lesion (transitional zone or peripheral zone or overlap between both zones), and lesion volume can predict csPCa after combined targeted and systematic biopsy in these patients. This can potentially help guide selection of patients with PI-RADS 3 lesions for biopsy in the future.

Materials and Methods

Consecutive patients were registered into a prospective institutional review board-approved database (DSRB 2015/01252) assessing MRI-targeted prostate biopsy in our institution. We reviewed patients who underwent biopsy from May 1, 2016 to June 30, 2017. Inclusion criteria for our study were patients with at least one PI-RADS 3 or higher lesion on mpMRI and who underwent both targeted and systematic prostatic biopsies in the same session. All these patients had either a raised serum PSA and/or suspicious digital rectal examination and/or previous negative systematic TRUS prostate biopsy. Patients who had undergone previous PCa treatment were excluded from our study.

All the patients in our study underwent mpMRI in accordance with PI-RADS v2 recommendations.⁹ All scans were performed on a 3 Tesla (T) MR scanner (TrioTIM, Siemens Healthcare) with a phased-array surface coil and without an endorectal coil. Multiparametric imaging combining axial, sagittal, and coronal T2-weighted, axial diffusion-weighted (b = 0,800,1500 seconds/mm²), and dynamic contrast-enhanced imaging (10 mL of gadoterate meglumine injected intravenously at 2.5 mL/second, axial VIBE with temporal resolution of 8–10 seconds) was used to assess for the likelihood of cancer. Two experienced uroradiologists with 10 years and 3 years' experience, respectively, in interpreting mpMRI reviewed all images. They also segmented the images and marked out the location of the suspicious lesion(s) (DynaCAD; Invivo).

Targeted biopsies were performed with the UroNav MRI-TRUS fusion system under local anesthesia. In brief, an end-firing endorectal probe (Philips) with a disposable needle guide mounted with a passive electromagnetic tracking sensor was introduced into the rectum. An electromagnetic field generator was placed above the pelvis and permitted real-time tracking of the endorectal probe needle guide. Next, a two-dimensional axial TRUS sweep was used to reconstruct a three-dimentional ultrasound volume that could be nonrigidly registered with the previously acquired axial T2-weighted MRI data. Targeted lesions were semiautomatically superimposed on the real-time TRUS image, allowing for real-time MRI-TRUS fusion biopsy. Each lesion was sampled in both axial and sagittal planes for a total of three cores per lesion. This was followed in the same session by a systematic 12-core biopsy in a double-sextant template of biopsies from the lateral and medial aspects of the base, mid, and apical prostate on the left and right side.

Criteria described by the standards of reporting for MRI-targeted biopsy studies consortium were followed in reporting this study.¹⁴ In patients with multiple lesions, an index lesion was determined according to PI-RADS v2. The index lesion was the one with the highest PI-RADS score. If an equal PI-RADS score was assigned to two or more lesions, the index lesion was the one that showed EPE. If none of the lesions demonstrated EPE, the largest tumor was considered the index lesion. All statistical analyses were performed using Stata version 15.0 (StataCorp, College Station, TX), Two-sided statistical significance was defined as p < 0.05.

Results

There were 115 patients included in this study. The vast majority (92%) of the patients were Chinese (n = 106). The median age was 69 years old [interquartile range (IQR) 65–74]. The median PSA was 8.7 ng/mL (IQR 6.2–13.9), median prostate volume was 56 cc (IQR 40–82), and median PSAD was 0.16 ng/mL/mL (IQR 0.11–0.27). The median time from mpMRI to biopsy was 48 days (IQR 32–110). Seventy-four patients (64%) had a previous negative systematic TRUS prostate biopsy, 28 (24%) patients were undergoing their first prostate biopsy, and 13 (11%) patients had known D'Amico low-risk PCa for which they were on active surveillance (AS). The number of patients with at least one PI-RADS 3, 4, or 5 lesions was 70 (61%), 34 (30%), and 11 (10%), respectively. A total of 169 lesions were biopsied and the full patient demographics are detailed in Table 1.

Table 1.

Patient Demographics

	n (115)
Age, median (IQR), years	69 (65–74)
PSA, median (IQR), ng/mL	8.7 (6.2–13.9)
Prostate volume, median (IQR), cc	56 (40–82)
PSAD, median (IQR), ng/mL/mL	0.16 (0.11–0.27)
Time from mpMRI to biopsy, median (IQR), days	48 (32–110)
Prior negative biopsy, n (%)	74 (64.3)
No prior biopsy, n (%)	28 (24.3)
On active surveillance (known low-risk PCa), n (%)	13 (11.3)
PI-RADS score of index lesion, n (%)
PI-RADS 3	70 (60.9)
PI-RADS 4	34 (29.6)
PI-RADS 5	11 (9.6)
Total No. of targeted lesions, n	169
Patients with one target, n (%)	65 (56.5)
Patients with two targets, n (%)	46 (40.0)
Patients with three or more targets, n (%)	4 (3.5)
Biopsies per target, median (IQR)	3 (1–3)

IQR = interquartile range; mpMRI = multiparametric MRI; PCa = prostate cancer; PI-RADS = Prostate Imaging Reporting and Data System; PSA = prostate-specific antigen; PSAD = PSA density.

Biopsy results

PCa was detected in 44% (51/115) and csPCa in 35% (40/115) of all patients in our study. Targeted biopsies detected significantly less Gleason 6 cancers than systematic biopsies (5.2% vs 17.4%, p < 0.01). Detailed biopsy results are shown in Table 2. Compared with systematic biopsies, targeted biopsies demonstrated significantly higher sensitivity (88% vs 60%, p < 0.01), specificity (92% vs 73%, p < 0.01), positive predictive value (PPV, 85% vs 55%, p < 0.01), and negative predictive value (NPV, 93% vs 77%, p < 0.01) for the detection of csPCa. However, if only targeted biopsy was performed, five (12.5%) cases of csPCa would have been missed. In contrast, systematic biopsy missed 16 (40%) cases of csPCa. The diagnostic accuracy of targeted and systematic biopsies is detailed in Table 3.

Table 2.

Prostate Cancer Detection Rates

		Detection of all PCa		Detection of csPCa		Detection of Gleason sum 6 PCa
PI-RADS score	n	Targeted biopsy, % (n)	Systematic biopsy, % (n)	Targeted biopsy, % (n)	Systematic biopsy, % (n)	Targeted biopsy, % (n)	Systematic biopsy, % (n)
3	70	21.4 (15)	25.7 (18)	15.7 (11)	12.9 (9)	5.7 (4)	12.9 (9)
4	34	52.9 (18)	55.9 (19)	47.1 (16)	26.5 (9)	5.9 (2)	29.4 (10)
5	11	72.7 (8)	63.6 (7)	72.7 (8)	54.6 (6)	0 (0)	9.1 (1)
Overall	115	35.7 (41)	38.3 (44)	30.4 (35)	20.9 (24)	5.2 (6)	17.4 (20)

csPCa = clinically significant prostate cancer.

Table 3.

Diagnostic Accuracy of Targeted and Systematic Biopsy for Clinically Significant Prostate Cancer

	Systematic biopsy,% (95% CI)	Targeted biopsy, % (95% CI)	p
Sensitivity	60 (43–75)	88 (73–96)	<0.01
Specificity	73 (62–83)	92 (83–97)	<0.01
PPV	55 (43–65)	85 (73–93)	<0.01
NPV	77 (70–84)	93 (86–97)	<0.01

CI = confidence interval; NPV = negative predictive value; PPV = positive predictive value.

Table 4 details the 64 cases wherein no PCa was detected. No pathology/benign prostatic tissue was found in 41%, 24%, and 9% of PI-RADS 3, 4, and 5 lesions, respectively. The next most common cause of a negative targeted biopsy was prostatitis/inflammation, which was reported in 30%, 3%, and 0% of PI-RADS 3, 4, and 5 lesions, respectively.

Table 4.

Pathology of Negative Targeted Biopsies

	PI-RADS 3 (n = 70)	PI-RADS 4 (n = 34)	PI-RADS 5 (n = 11)
Prostatitis, n (%)	21 (30)	1 (2.9)	0 (0)
Granulomatous inflammation, n (%)	0 (0)	1 (2.9)	1 (9.1)
High-grade prostatic intraepithelial neoplasia, n (%)	0 (0)	1 (2.9)	0 (0)
Atypical glands, n (%)	1 (1.4)	0 (0)	0 (0)
No pathology, n (%)	29 (41.4)	8 (23.5)	1 (9.1)

Predictive factors for csPCa in PI-RADS 3 lesions

As the majority of the patients in our study (62%) had an index lesion graded as PI-RADS 3, we did a subgroup analysis of these patients to examine whether utilization of factors, such as PHI, PSAD, PSA, prostate volume, location of the index lesion (transitional zone vs peripheral zone vs overlap between both zones), and lesion volume can improve the predictive ability for csPCa after combined targeted and systematic biopsy.

Only 35 of our 70 patients with a PI-RADS 3 index lesion had a serum PHI performed. The receiver operating characteristics curve analysis for csPCa showed that the area under the curve (AUC) values of PHI and PSAD were 0.77 [95% confidence interval (CI) 0.58–0.95] and 0.61 (95% CI 0.38–0.84), respectively, which were much higher than PSA (AUC 0.52, 95% CI 0.27–0.77), index lesion location (AUC 0.54, 95% CI 0.34–0.74), lesion volume (AUC 0.34, 95% CI 0.09–0.59), and prostate volume (AUC 0.21, 95% CI 0.01–0.42).

To determine the optimal PSAD and PHI level to predict csPCa, we tested different cutoff values in detecting or missing csPCa. We found that PSAD ≥0.10 ng/mL/mL would have detected all but one tumor, with an NPV of 93% and sensitivity of 92%, while allowing 20% of patients to avoid biopsy. For PHI, we found the optimal cutoff to be ≥27, which would allow 34% of patients to avoid biopsy. At this level, no csPCa was missed and both sensitivity and NPV were 100%. Table 5 details the diagnostic accuracy of incorporating different PSAD and PHI cutoffs for the detection of csPCa.

Table 5.

Diagnostic Accuracy of Different Prostate-Specific Antigen Density and Prostate Health Index Cutoffs for Patients with Prostate Imaging Reporting and Data System 3 Index Lesions

Decision to biopsy	Sensitivity, % (95% CI)	Specificity, % (95% CI)	PPV, % (95% CI)	NPV, % (95% CI)	% who avoid biopsy	% of missed csPCa
PSAD ≥0.10	92 (64–100)	23 (13–36)	21 (18–25)	93 (65–99)	20	8
PSAD ≥0.12	77 (46–95)	30 (18–43)	20 (15–26)	85 (66–94)	29	23
PSAD ≥0.15	46 (19–75)	49 (36–63)	17 (10–28)	80 (69–88)	50	54
PHI ≥27	100 (63–100)	44 (25–65)	35 (28–43)	100 (NA)	34	0
PHI ≥30	75 (35–97)	52 (32–71)	32 (21–45)	88 (67–96)	46	25
PHI ≥35	63 (24–91)	74 (54–89)	42 (24–62)	87 (73–94)	66	38

PHI = prostate health index.

Discussion

To the best of our knowledge, our study represents the first published report on MRI-TRUS fusion prostate biopsy in Southeast Asian men. The vast majority (92%) of our patients were Chinese. Most of our patients (64%) had a previous negative prostate biopsy and most of them (61%) had an index lesion graded as PI-RADS 3. As expected, csPCa detection increases with a higher PI-RADS score. In our study, the detection rates of csPCa based on PI-RADS score are consistent with that of published literature.

The National Cancer Institute group, which utilizes the same UroNav MRI-TRUS fusion system as us, reported csPCa detection rates of 12%, 22.1%, and 72.4% for PI-RADS 3, 4, and 5 lesions, respectively, in Mehralivand and colleagues' recent review of 339 patients.¹² In another multicenter study including 487 patients with previous negative prostate biopsies who underwent MRI fusion-targeted and systematic biopsies, Hansen and colleagues reported that csPCa was found in 20% of patients with PI-RADS 3 lesions on targeted biopsy, and 32% and 70% for PI-RADS 4 and PI-RADS 5 lesions, respectively.¹³ In the largest MRI-targeted biopsy study by Venderink et al, which involved 1057 patients, they found csPCa in 17%, 35%, and 67% of patients with PI-RADS 3, 4, and 5 lesions, respectively.⁶ The cancer detection rates for csPCa in these studies compare favorably with our detection rates of 15.7%, 47.1%, and 72.7% for targeted biopsies of PI-RADS 3, 4, and 5 lesions, respectively.

In our study, targeted biopsy was significantly superior to systematic biopsy for the detection of csPCa. The sensitivity, specificity, PPV, and NPV of targeted biopsy were also significantly superior to those of systematic biopsy. These results are largely similar to the results reported by other studies performed on predominantly Caucasian populations.^4
–6

This study also highlights the current challenges in the management of PI-RADS 3 lesions, which have relatively low rates of csPCa and may be subject to over investigation.^6,12,13 We believe that it may be possible to utilize PSAD and PHI to better predict for csPCa in patients with PI-RADS 3 lesions, to decide who should undergo targeted biopsy. For PSAD, we found that a cutoff of ≥0.10 ng/mL/mL to be the best predictor for csPCa compared with all other PSADs. In their study of 288 biopsy-naive patients, Washino and colleagues reported that no patients with PI-RADS score of ≤3 and PSAD of <0.15 ng/mL/mL had csPCa.¹⁵ Hansen et al. similarly found that a PSAD cutoff of >0.15 ng/mL/mL significantly improved the PPV for Gleason score 7 to 10 cancers when performing targeted biopsy for PI-RADS 3 lesions.¹³ In their multicenter study of 487 patients, the PPV improved from 11% for patients with PSAD ≤0.15 ng/mL/mL to 33% for patients with PSAD >0.15 ng/mL/mL. Venderink and colleagues, in their study of 1057 patients undergoing MRI-targeted biopsies, confirmed the ability of PSAD to predict csPCa in patients with PI-RADS 3 lesions.⁶ They reported that using a PSAD cutoff of ≥0.15 ng/mL/mL for patients with PI-RADS 3 lesions results in 42% of patients avoiding targeted biopsy, of which 6% will have a missed diagnosis of csPCa. In their study, if a more stringent cutoff of PSAD of ≥0.12 ng/mL/mL was used instead, no csPCa will be missed (while avoiding biopsy in 26% of patients).

PHI has shown promise as a more accurate biomarker than PSA for predicting csPCa and is Food and Drug Administration approved in the United States for use in men with PSA 4–10 ng/mL and a normal digital rectal examination considering biopsy.¹⁶ Despite this, PHI has not yet become widely clinically available and we sought to assess its clinical utility in predicting csPCa in men with PI-RADS 3 lesions undergoing MRI-TRUS fusion-targeted biopsy. In our study, we found that PHI had the highest predictive performance for csPCa with AUC of 0.77, which was superior to that of PSAD. Unfortunately, there is a paucity of studies evaluating the incremental value of adding PHI to mpMRI for the detection of csPCa in patients undergoing targeted biopsy. In one study, Gnanapragasam and colleagues reviewed 279 men undergoing repeat prostate biopsy, and reported that adding PHI to mpMRI improved the prediction of csPCa (AUC 0.75) compared with mpMRI with PSA alone (AUC 0.69).¹⁷ They added that the threshold of ≥35 had the highest NPV of 0.97 for excluding csPCa. Tosoian and colleagues from Johns Hopkins reported that none of the 15 men with PI-RADS ≤3 lesions and PHI <27 had Gleason grade group ≥2 cancer on biopsy, as compared with 29% (8 of 28) of men with PI-RADS ≤3 lesions and PHI >27 who had Gleason grade group ≥2 cancer detected.¹⁸ This PHI cutoff is exactly the same as what we found in our study.

Thirteen patients in our study were on AS for known D'Amico low-risk PCa. Six of them (46%) were upgraded to csPCa after MRI-TRUS fusion prostate biopsy. However, as this group of patients made up a very small proportion (11%) of our study population, further analysis was not done but they will be reported in the future once accrual increases. We note that MRI of prostate is increasingly being utilized in various AS protocols. A systematic review by Schoots et al. reported that a positive MRI was more likely to be associated with upgrading at radical prostatectomy than a negative MRI (43% vs 27%) in men on AS.¹⁹ Utilizing MRI-TRUS fusion prostate biopsy in their cohort of 166 patients on AS, Frye and colleagues reported that fusion biopsy significantly outperformed systematic biopsy for the detection of pathologic progression, detecting 26% more cases.²⁰ In addition, Alberts et al. reported on the incremental role of PSAD with MRI in patients on AS.²¹ In their cohort of 210 men, about a quarter of patients had upgrading on MRI-targeted biopsy. However, they reported that none of the men with PI-RADS score of 1–3 and PSAD of <0.15 ng/mL/mL had upgrading of cancer.

Our study has a number of limitations. The majority of our patients (64%) had one or more previous biopsies. Thus our results may not be applicable to the biopsy-naive group of patients. However, routine mpMRI in biopsy-naive patients is not widely practiced in our healthcare setting because of concerns with regard to rising healthcare costs. Second, patients with PI-RADS 1 or 2 lesions on mpMRI were excluded from our study, potentially reducing true negatives and the specificity and NPV derived from our study. Data from a systematic review by Futterer et al. reported that a negative MRI has a NPV of up to 98% for csPCa.²² However, a more recent systematic review by Moldovan et al. reported a slightly lower median NPV of 82.4% for overall PCa and 88.1% for csPCa.²³ In view of the high NPV of a negative mpMRI, the cohort of patients with negative mpMRI excluded from our study is unlikely to harbor many cases of csPCa and, therefore, unlikely to have affected our outcomes significantly. Third, the same clinician performed both the targeted and systematic biopsies and thus was not blinded to the location of the suspicious lesion(s). This is in contrast to another targeted biopsy study utilizing the UroNav MRI-TRUS fusion system reported by Siddiqui and colleagues,⁵ where one physician performed the targeted biopsy, and the systematic biopsy was done by a different physician who was not aware of the MRI lesion locations. Our method could have affected the results of the systematic biopsies as the clinician may preferentially avoid the larger suspicious lesion(s) during the systematic biopsy. Conversely, there may have been a tendency for the clinician to direct the biopsy needle during systematic biopsy toward the area of smaller lesions because of cognitive bias. Fourth, we used the combined targeted and systematic biopsies as the reference standard for PCa and csPCa. This is in contrast to some other studies that used whole-gland prostatectomy specimens^5,24,25 or template prostate mapping biopsies,^7,26
–28 where the prostate is sampled every 5 mm, as the “gold standard.” This could have affected the diagnostic accuracy analyses in our study. Finally, as our study was conducted in a single institution and had a relatively small sample size, the results may not be generalizable to other centers.

Conclusions

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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