Targeted and Systematic Biopsy for the Diagnosis and Management of Prostate Cancer — A Case for Lesion Targeted-Only Biopsies

Clinical Oncology 32 (2020) 136e143 Contents lists available at ScienceDirect

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Targeted and Systematic Biopsy for the Diagnosis and Management of Prostate Cancer d A Case for Lesion Targeted-Only Biopsies J.O. Tam, H.U. Ahmed Imperial Prostate, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London and Imperial College Healthcare NHS Trust, London, UK Received 31 October 2019; received in revised form 11 December 2019; accepted 7 January 2020

Abstract For much of the 1990s, transrectal ultrasound systematic biopsy was the standard approach for prostate cancer diagnosis. However, in the past decade multiparametric magnetic resonance imaging, multiparametric ultrasound and image fusion targeting have come to the fore. Here we present the state-of-the-art diagnostic strategies in prostate cancer detection and examine the case for target-only biopsy, as well as the benefits and limitations. Ó 2020 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.

Key words: image fusion; multiparametric magnetic resonance imaging; prostate cancer; targeted prostate biopsy; ultrasound

Introduction Prostate cancer is unique among cancers because of the slow indolent nature of the disease. According to Cancer Research UK [1], the peak rate of prostate cancer deaths is over 90 years old, whereas the peak rate of incidence is 75e79 years old [2]. This means that some men who are diagnosed with prostate cancer may not have clinically significant cancer within their lifetime, as other medical conditions are more likely than prostate cancer to cause morbidity and mortality. The gold standard for prostate cancer diagnosis is histological diagnosis of prostate biopsies. However, the problem of sampling less than 1% of the prostate with biopsy strategies leaves a large volume of tissue that has not been evaluated and therefore risks missing clinically significant prostate cancer. This may be less relevant if the patient is recommended for whole-gland therapy, but might be a problem in focal therapy. Data on the number of foci detected on magnetic resonance imaging (MRI) and whole-mount histopathology are summarised in Table 1. Author for correspondence: J.O. Tam, Office 128, 1st Floor Laboratories, Imperial Centre for Translational and Experimental Medicine, Hammersmith Campus, Imperial College London, London, W12 0NN, UK. E-mail address: [email protected] (J.O. Tam).

There are two main approaches to obtain prostate samples. The first was the transperineal biopsy described by Barringer [7] in 1922; the second was the transrectal biopsy described by Astraldi [8] in 1937. Early biopsies were guided with digital rectal examinations. Takahashi and Ouchi [9] improved accuracy by using ultrasound to guide the biopsy, but the images were poor. It was not until Watanabe et al. [10] showed the first clinically useful transrectal ultrasound biopsy images in 1968 that ultrasound-directed biopsies became common. In 1989, Hodge et al. [11] described the use of six-quadrant systematic prostate needle biopsy, which further improved the detection of prostate cancer of any grade and led to the widespread use of systematic and saturation biopsies, commonly transrectally. For much of the 1990s, this remained the standard approach for prostate biopsies; nowadays, standard systematic biopsy procedures continue to use this 12-core system. MRI-guided in-bore biopsy was first published in a case report by D’Amico et al. [12] in 2000. Since then, many trials have compared the various diagnostic modalities and, as a result, the latest guidelines from the 2019 National Institute for Health and Care Excellence [13], the 2019 European Association of Urology guidelines and the 2019 American Urological Association guidelines recommend offering multiparametric MRI as a first-line prostate cancer diagnostic test before biopsy in patients with a clinical

https://doi.org/10.1016/j.clon.2020.01.001 0936-6555/Ó 2020 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.

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Table 1 Percentage of one, two, three or four or more prostate lesions detected at prostatectomy Reference

Country

Number of patients

Percentage of prostate lesions detected by histopathology at prostatectomy 1

2

3


4

[3] [4] [5] [6]

USA USA South Korea USA

122 71 762 588

36.1% 33.8% 39.5% 36.7%

23.8% 38.0% 37.0% 33.7%

19.7% 12.7% 18.8% 18.7%

20.4% 15.5%* 4.7%* 10.9%*

*

Original data were split into four and five or more lesions. For comparative purposes, these have been combined.

suspicion. The largest lesion by volume detected on MRI is called the index lesion and is thought to be the one with the highest grade and likelihood of metastasis [14]. Systematic biopsies are recommended alongside targeted biopsies to MRI suspicious areas. The current biopsy strategies are summarised in Table 2. Here we present the case for targeted-only biopsies in terms of cancer detection rates, pathological upgrading at radical prostatectomy, complication rate and practicalities compared with conducting targeted with systematic (nontargeted) biopsies.

The Case for Targeted-Only Prostate Biopsy Cancer Detection Rates Systematic 12-core biopsy benefits from widespread use, ease and speed of access. Preparation time is minimal, and the procedure is completed in minutes. However, we know that this approach misses significant cancers due to the inability to evaluate the whole of the prostate and a propensity to under-sample certain parts of the prostate (apex, anterior). In a study of 289 men with prior negative transrectal ultrasound biopsy, 78% of missed lesions by the prior negative transrectal ultrasound were in the anterior region. At repeat transrectal ultrasound biopsy, 84% of missed lesions were again in the anterior or apical regions [15]. In 2017, the multicentre PROMIS trial [16] compared cancer detection rates of transrectal ultrasound and multiparametric MRI against a reference template prostate mapping biopsy on 576 patients. The results showed that multiparametric MRI as a first-line test may allow 27% of men to avoid an immediate biopsy while improving the diagnosis of clinically significant cancer and reducing the detection of clinically insignificant cancers. In fact, the sensitivity for significant cancer (defined as Gleason
4 þ 3 or more or a maximum cancer core length involvement of 6 mm or more of any grade) of 12-core transrectal systematic biopsy compared with multiparametric MRI was 48% (95% confidence interval 42e55) and 93% (95% confidence interval 88e96), respectively. Even for any Gleason 3 þ 4 disease or more, sensitivity was 60% (95% confidence interval 55e65) and 87% (95% confidence interval 83e90), respectively. A recent Cochrane systematic review used a baseline cancer prevalence of 30% and estimated from eight studies that the MRI pathway had sensitivity of 72% and specificity

of 96% with pooled rates of 216 true positives, 28 false positives, 672 true negatives and 84 false negatives per 1000 men, whereas estimates from four studies of systematic biopsy had sensitivity of 63%, specificity of 100% and pooled rates of 189 true positives, 0 false positives, 700 true negatives and 111 false negatives per 1000 men [17]. The authors concluded that the MRI pathway had equal or better detection rates when compared with systematic biopsy, but reduced findings of insignificant cancer. The cancer detection rates for targeted biopsy increases with the number of cores taken, but compared with systematic biopsy, far fewer cores are required. In one study, detection rates from one to five cores were 69% (one core), 84% (two cores), 91% (three cores), 96% (four cores) and 99% (five cores), respectively, for Gleason 3 þ 3 or greater [18]. The SmartTarget Biopsy Trial [19] compared 141 men who had undergone a prior transrectal 12-core systematic biopsy and multiparametric MRI. If they had a discrete lesion on multiparametric MRI, patients were randomised to transperineal visual estimation targeted biopsy or transperineal MRIeultrasound fusion targeted biopsy. Significant cancer was detected in 72% by each strategy alone, whereas both strategies combined detected 86% of significant cancers, with each missing 13 cases that the other had detected. There was no difference in complications reported or quality of life assessments between strategies at a median follow-up of 10.5 weeks. This suggests that visual estimation and image fusion targeting, rather than being separate, should be combined to complement one another. This was also supported by the PICTURE study [20]. Recently, we have shown that the use of non-targeted biopsies might be risk stratified dependent on what the targeted biopsy risk is. Of the 357 men who underwent nontargeted biopsies, three (0.8%) had clinically significant prostate cancer exclusively in non-targeted cores, with no evidence of cancer in targeted cores. Overall, 32/357 (9.0%) had clinically significant prostate cancer in non-targeted biopsies regardless of the targeted biopsy findings. Clinically insignificant disease in non-targeted biopsies was detected in 93/357 men (26.1%) [21].

Cancer Upgrading In the past, 12-core systematic biopsy was the only way to sample areas of the prostate but can increase the risk of diagnosing clinically insignificant cancer. It also

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Table 2 Summary of targeting strategies and biopsy approaches. Depending on biopsy approach, the orientation of the cores may differ as transrectal biopsies sample from the posterior towards the anterior, whereas transperineal biopsies sample axially from the apex towards the base of the prostate* Targeting strategy

Summary of technique

MRIeultrasound fusion

The use of software and hardware to superimpose precontoured multiparametric MR images or their contours onto live ultrasound images to facilitate accurate targeting The biopsy operator looks at the multiparametric MR images on one screen (either in the same room or elsewhere) and estimates where to deploy the needles when carrying out the targeted biopsies with the use of live ultrasound images alone Usually >10 cores are taken from each area of the prostate under transrectal ultrasound guidance in order to sample the prostate at apex, mid-gland and base on both sides of the prostate. The anterior area is often not sampled. MRI is not used although hypoechoic ultrasound lesions are sometimes targeted A transrectal or transperineal technique in which the ultrasound probe is placed in the rectum and not fixed by a mechanical device. The biopsy is also deployed using simple mechanical guides (plastic or metal) attached to the ultrasound probe or sometimes free of the ultrasound probe. Image fusion or visual estimation can be used A transperineal technique of systematically sampling the whole prostate. A 5 mm spaced brachytherapy type grid is placed over the perineum and biopsies taken every 5 mm (mapping) or every 10e15 mm using a variety of described zonal sampling strategies (sectoral, Ginsberg, Barzell, modified Barzell) Using a grid set-up, targeted biopsies (visual estimation or image fusion) are taken with some form of non-targeted systematic biopsies (mapping, sectoral, Ginsberg, Barzell, modified Barzell) or limited sampling of the peripheral zones (only to be concordant with 10e12 systematic sampling)

Visual estimation or registration MRI

Systematic transrectal (or sometimes referred to as ‘random’)

Freehand

Template (systematic transperineal)

Template targeting

MRI, magnetic resonance imaging. * This table is not exhaustive and does not include some targeting strategies (such as contrast-enhanced multiparametric ultrasound or MRI in-bore biopsies).

misclassified disease as low risk, leading to a significant upgrading on repeat biopsy in men who adopted active surveillance. Reports of Gleason upgrading occurs in between 28 and 49% of men having Gleason 6 on an initial test (Table 3). In one direct head-to-head study of 582 patients who underwent both MRIeultrasound fusion targeted biopsy and systematic biopsy (but without radical prostatectomy whole-mount specimens), cancer was detected in 54% of this cohort using both methods. The addition of MRIeultrasound fusion targeting led to Gleason upgrading in 32% of cases, whereas systematic biopsy led to only 26% upgrading [27]. Comparable data recently published in the past few years on MRIeultrasound fusion biopsies seems to show lower rates of cancer upgrading in MRIeultrasound fusion biopsies compared with systematic biopsies (Table 4). One multicentre study recently retrospectively

compared concordance between systematic biopsy and MRIeultrasound fusion targeted biopsy using radical prostatectomy as a reference standard in 443 patients. Using the International Society of Urological Pathology grading system (grade 1 Gleason 3 þ 3, grade 2 Gleason 3 þ 4, grade 3 Gleason 4 þ 3, grade 4 Gleason 4 þ 4, 3 þ 5 or 5 þ 3, grade 5 Gleason 9e10), they found that concordance for systematic biopsy reached 49.4%, MRIeultrasound fusion targeting 51.2% and systematic and MRIeultrasound fusion biopsy combined 63.2% for any prostate cancer. When significant cancer was defined as grade 2 or more, these rates of concordance were 41.2%, 48.3% and 56.7%, respectively. MRIeultrasound fusion targeting, total number of cores and previous biopsies were independent predictive factors for concordance [33]. Another study retrospectively analysed 135 patients who underwent prebiopsy MRI,

Table 3 Patients on active surveillance with upgraded cancer diagnosis after initial systematic biopsy suggesting low-risk cancer Reference

Location

Number of patients

Reclassification method

Patients upgraded

[22] [23]

Netherlands USA

2494 1298

Prostatectomy Re-biopsy

[24] [25] [26] Klotz et al., 2019*

Korea Sweden Turkey Canada

60 474 627 273

Prostatectomy Re-biopsy Prostatectomy Re-biopsy

28% 26% (10 year) 31% (15 year) 40% 25% 49.3% 29%

*

ASIST study (see [22]).

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Table 4 Studies reporting cancer upgrading in magnetic resonance imaging (MRI)eultrasound fusion biopsy versus systematic biopsy for all Gleason grades using radical prostatectomy histopathology as the reference template. It is important to note that the number of cores taken in systematic biopsy varies between studies and sometimes even within studies, but ranges from 10 to 20 cores depending on the operator Reference Location [28] [29] [30] [31] [32] *

Number of patients

Systematic biopsy upgrading MRIeultrasound fusion biopsy upgrading

Germany 366 33.5% 11 countriesy 57 14.8% Brazil 73 MRIeultrasound fusion biopsy 31.5% 89 systematic biopsy Italy 246 39.3% USA 170 36.4%

31.7% 16.7% 16.4% 6.8% 24.1%

* Siddiqui et al. collated data from biopsy samples of 1003 patients. Only 170 patients underwent radical prostatectomy, so only data from those 170 patients have been included. Upgraded groups for MRIeultrasound fusion biopsy compared with whole-mount pathology: no cancer to low-risk cancer 14, no cancer to intermediate-risk cancer 1, no cancer to high-risk cancer 2, low-risk cancer to intermediate-risk cancer 13, low-risk cancer to high-risk cancer 6, intermediate-risk cancer to high-risk cancer 5, sum of all risk groups upgrading 14 þ 1 þ 2 þ 13 þ 6 þ 5 ¼ 41 (24.1% of whole prostatectomy cohort). Upgraded groups for systematic biopsy compared with whole-mount pathology: no cancer to low-risk cancer 8, no cancer to intermediate-risk cancer 4, no cancer to high-risk cancer 8, low-risk cancer to intermediate-risk cancer 21, low-risk cancer to high-risk cancer 13, intermediate-risk cancer to high-risk cancer 8, sum of all risk groups upgrading 8 þ 4 þ 8 þ 21 þ 13 þ 8 ¼ 62 (36.4% of whole prostatectomy cohort). y Finland, Argentina, Italy, USA, Germany, UK, Netherlands, Canada, Belgium, France, Switzerland.

MRIeultrasound fusion targeted biopsy and robotic radical prostatectomy and found concordance between the index lesion and radical prostatectomy specimens of 95%, whereas the primary Gleason pattern on biopsy and at radical prostatectomy reached 90%. Unfortunately, data for systematic biopsy were not available for this study for comparison as it was a retrospective study [34]. In one paper that compared MRIeultrasound fusion biopsy with Gleason score directly in 125 patients using radical prostatectomy as reference, cancer was detected in 115 patients and primary Gleason grade, secondary Gleason grade and Gleason score reached concordance levels of 90%, 59% and 67%, respectively. The authors found that the maximal Gleason score was accurate for 70% of patients, with accuracy increasing on low Gleason and high Prostate Imaging-Reporting and Data System (PI-RADS) scoring tumours [35]. Another study looked at saturation biopsies (defined as biopsies taken every 6 mm along the long axis of the index lesion) for 86 patients versus non-saturated biopsies (only one core taken from the index lesion) for 122 patients and the risk of upgrading in radical prostatectomy. The median number of biopsy cores per index lesion was four versus two in the saturation versus non-saturation group. Gleason upgrading for systematic, fusion, and combined fusion and systematic biopsy was 40.9%, 23% and 13.8%, respectively. The risk of upgrading in the combined fusion and systematic biopsy group was lower in the saturated (7%) than in the non-saturated group (18%). In the saturated group, fusion biopsy results were upgraded in 20.9% compared with 36.9% in the non-saturated group, with risk category upgrading reported at 14% and 30.3%, respectively. This suggests that saturation biopsies of the index lesion significantly reduce the risk of upgrading [36]. A systematic review and meta-analysis compiled data from 10 studies comprising 1215 patients from three retrospective cohorts, six paired cohort studies and one randomised control trial to examine the concordance

between biopsy technique and radical prostatectomy. The authors found that pathological upgrading was less likely with targeted biopsy compared with systematic biopsy alone without an increase in downgrading. The targeted biopsy Gleason score was upgraded in 23.3%, whereas the systematic biopsy was upgraded in 42.7% of the studies examined [37]. For men under active surveillance, the ASIST study looked at 259 men who were randomised to an MRIeultrasound fusion targeting biopsy or a 12-core systematic biopsy. Interestingly, they initially reported that the addition of MRI with targeted biopsies to systematic biopsies did not increase pathological upgrading [38]. However, more recent results from the same study found that there was a 50% reduction in active surveillance failure and a significant reduction in cancer upgrading (23% in the systematic biopsy arm versus 9.9% in the MRIeultrasound fusion biopsy arm) by the addition of MRIeultrasound fusion biopsy [39]. Complication Rates and Practical Limitations MRIeultrasound fusion targeted biopsy has improved precision in biopsy, thereby reducing the number of biopsy cores needed and the risk of complications. A study that compared 144 patients who underwent 12-core transrectal systematic biopsy and 98 patients who underwent freehand transperineal MRIeultrasound fusion biopsy found no significant difference between infection and rectal bleeding rates requiring admission, haematuria, lower urinary tract symptoms, dysuria or acute urinary retention, but reported that rates of infection (11.1% transrectal versus 3.1% transperineal, P ¼ 0.022) and rectal bleeding (1.4% transrectal versus 0% transperineal, P < 0.001) were higher in the transrectal group, whereas reported rates of perineal swelling (2.1% transrectal versus 10.2% transperineal, P ¼ 0.006) were higher in the transperineal group [40]. In one prospective non-randomised trial of 262 patients, 203

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Fig 1. Intraoperative contouring with biopsy targeting and three-dimensional reconstruction. The red outline shows the prostate, whereas the blue outline shows the prostate cancer lesion.

patients underwent systematic biopsy and 59 MRIeultrasound fusion targeting, with median cores taken of 12 and three for each modality, respectively. Patients were given questionnaires on pain, discomfort and other non-infectious complications to complete immediately after the biopsy and at 30 days. The results showed that at day 30 more patients in the systematic biopsy cohort (34%) complained of pain compared with those in the fusion biopsy group (20%). Haematuria was reported in 44% of fusion biopsy cases and 69% of systematic biopsy cases [41]. Despite improvements in the detection of clinically significant cancer, MRIeultrasound fusion biopsy is not without its limitations [42]. Twelve-core systematic biopsy is usually carried out with the patient awake under local anaesthetic peri-prostatic block, whereas MRIeultrasound fusion biopsy may require sedation or general anaesthetic if a transperineal approach is taken. MRIeultrasound fusion biopsy uses software to fuse MR images taken before the procedure with live ultrasound imaging to target lesions accurately (Figures 1 and 2). However, this requires

significant preoperative planning and MRI contouring, which may limit widespread usage in different centres where MRI provision is insufficient to meet demand. Furthermore, MRIeultrasound fusion targeting may not provide information about secondary lesions, which may be relevant in focal therapy or for planning of nerve-sparing prostatectomy. However, as smaller lesions not detected on MRI are less likely to harbour clinically significant cancer, one could argue that this risk is somewhat minimal. There are reports from the USA that MRIeultrasound fusion biopsy is more cost-effective in the long term, with the optimum screening strategy (defined as an incremental cost-effective ratio of $23 483 per quality-adjusted life years) recommending MRIeultrasound fusion biopsy for PIRADS
3 and no biopsy for PI-RADS < 3 [43]. The National Institute for Health and Care Excellence in the UK has published a detailed costebenefit analysis and in conclusion recommended multiparametric MRI as a first-line screening tool followed by biopsy both for clinical and cost-effectiveness. Other studies have shown similar

Fig 2. Intraoperative ultrasound fusion biopsy. Contouring is fused with live ultrasound during prostate biopsy. Here, the biopsy needle can clearly be seen sampling a core of the prostate (outlined in red) through the prostate cancer lesion (outlined in blue).

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findings in the Netherlands. Discussion of a full cost-benefit analysis is beyond the remit of this paper.

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for Sophiris Biocorp, Sonacare Inc., BTG/Galil and Boston Scientific for proctoring surgical procedures and clinical trial design and delivery.

Conclusion Appendix A. Supplementary data The traditional systematic 12-core biopsy has good cancer detection rates but is limited due to the random deployment of needles. Targeted biopsy e whether MRIeultrasound fusion or visual-estimation biopsy e improves the detection of clinically significant cancer while reducing insignificant cancer. Preliminary data seem to suggest that targeted biopsy results in reduced rates of cancer upgrading compared with systematic biopsies alone, as a result of increased detection of clinically significant cancers compared with systematic biopsy. Targeted biopsy provides the best overall diagnostic accuracy, despite the increased time, cost and data analysis required. Importantly, the change in how we diagnose prostate cancer, from a rather random sampling strategy to one that is directed to a clinical phenotype alone (with or without sampling of non-suspicious areas on imaging) will probably lead to changes in risk. Our current risk strata (whether D’Amico, National Comprehensive Cancer Network [NCCN], Cancer of the Prostate Risk Assessment [CAPRA], Epstein) are based on developing and validating thresholds of prostate-specific antigen, stage and biopsy parameters based on prostate-specific antigen unadjusted by prostate volume or tumour volume, clinical examination not prebiopsy MRI and random sampling of the prostate not accurate deployment of the needle through the centre of a suspicious lesion. We will need to recalibrate our risk models with this in mind. Indeed, we have shown that targeted biopsy can lead to a Wil Rogers phenomenon and must be wary not to overtreat those men who have higher burdens of cancer as a result of oversampling through targeted approaches [44]. A similar issue will probably arise from whole-body functional imaging, such as positron emission tomography or whole-body MRI, in the detection of metastatic disease [45].

Conflict of Interest The authors declare the following financial interests/ personal relationships which may be considered as potential competing interests: Tam is funded by the United Kingdom’s National Institute of Health Research (NIHR) Imperial Biomedical Research Centre. Ahmed’s research is supported by core funding from the United Kingdom’s National Institute of Health Research (NIHR) Imperial Biomedical Research Centre. Ahmed currently receives funding from the Wellcome Trust [grant number 204998/Z/ 16/Z], MRC (UK), Cancer Research UK, Prostate Cancer UK, The Urology Foundation, BMA Foundation, The Imperial Health Charity, Sonacare Inc., Trod Medical and Sophiris Biocorp for trials in prostate cancer. Ahmed receives an unrestricted grant from Sonacare Inc. and BTG/Galil for work in focal therapy. Ahmed is a paid medical consultant

Supplementary data to this article can be found online at https://doi.org/10.1016/j.clon.2020.01.001.

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