A Collaborative Initiative by the American Urological Association and the Society of Abdominal Radiology Prostate Disease Focus Panel.
AUA: Pat F. Fulgham, MD; Daniel B. Rukstalis, MD; Jonathan N. Rubenstein, MD; Samir S. Taneja, MD; Peter R. Carroll, MD; Peter A. Pinto, MD; Marc A. Bjurlin, DO, MSc; Scott Eggener, MD
SAR: Ismail Baris Turkbey, MD; Daniel J. Margolis, MD; Andrew B. Rosenkrantz, MD
Multi-parametric MRI (mpMRI) has been proven to be a valuable tool in the diagnostic and management pathway in men at risk of prostate cancer. The excellent resolution and high signal-to-noise ratio provided by MRI, combined with the functional measurements of water diffusion and contrast enhancement, improve insight into the underlying histopathology of the prostate. Enthusiasm in the urologic community for the use of prostate mpMRI is evident in the dramatic increase in utilization.1
Evolution of the mpMRI technique with guidance from the Prostate Imaging Reporting and Data System (PI-RADS) has standardized mpMRI interpretation and reporting.2 With advancing research, the utility of prostate mpMRI continues to progress. mpMRI of the prostate allows for risk stratification of men at risk for prostate cancer including its ability to predict cancer aggressiveness prior to biopsy.3 The pereformance of prostate mpMRI in men with no prior biopsy is now supported by randomized clinical trials, while its use in men with a prior negative biopsy continues to be endorsed by consensus statements and national guidelines.4–8 mpMRI is useful for prostate cancer staging and treatment planning, where it can impact decision making and guide therapy. Emerging data suggest MRI may further identify and risk stratify men who are candidates for active surveillance.9
The purpose of this paper is to update the prior AUA MRI of the Prostate, Standard Operating Procedure document by critically appraising the available evidence. Practical recommendations are made about how MRI can best be deployed by clinicians across the spectrum of prostate cancer care, risk assessment, and management. The Multi-parametric Prostate MRI Consensus Panel has performed a thorough literature review and examined the prostate MRI technique and parameters along with potential applications of this imaging modality in the diagnosis, staging, and management of men with clinically localized prostate cancer. Information on this subject is evolving so rapidly that in some cases there is not enough evidence available to make definitive recommendations based on data alone. Therefore, these recommendations are based in part on a critical review of the literature and in part on collective expert opinion.
Prostate mpMRI Technique
Prostate mpMRI is being increasingly used to guide prostate cancer clinical management. This growing interest in mpMRI has been accompanied by a significant variation and heterogeneity in image acquisition, interpretation, and pre-biopsy image processing, which can hinder patient care. To address these issues, the American College of Radiology (ACR), the European Society of Urogenital Radiology (ESUR), and the AdMeTech Foundation published basic guidelines for mpMRI acquisition and interpretation in early 2015.10 This document clearly stated that the technical details of prostate mpMRI, which ultimately affect the imaging protocol, should be tailored to the patient’s needs and the clinical questions raised by the referring physician. In this section, we will cover technical points such as equipment, basic parameters, image interpretation, and communication of these findings with urologists.
A. Equipment Specifications:
Prostate MRI can be obtained with a conventional 1.5Tesla (T) or high field 3.0T magnet with or without using an endorectal coil (ERC). Although there are some papers comparing these different techniques, there is as yet no prospective and randomized study addressing which equipment is superior in cancer detection and staging.11,12 We will group technical specifications as minimum and ideal standards:
1. Minimum Standards
3.0T magnet systems provide twice the signal-to-noise ratio (SNR) compared to 1.5T systems, which provides increased spatial and temporal resolution and results in improved image quality. Despite this difference, prostate mpMRI obtained at 1.5T can still yield diagnostic images for lesion detection.10 However, use of an ERC should be considered especially if older 1.5T systems are used or local staging is planned with newer 1.5T magnets. For 3.0T systems, per minimum standards, an ERC is not necessary for lesion detection. However, an ERC`s necessity for local staging is still under debate.
For non-ERC prostate MRIs, either at 1.5T or 3.0T, susceptibility to artifacts secondary to the presence of rectal gas can easily diminish image quality especially during diffusion-weighted MRI. Per minimum standards, patients should be asked to empty their bowel prior to prostate MRIs.10 This is of paramount importance for diagnostic image quality.
Use of 1.5T magnets (instead of 3.0T magnets) can be recommended in particular situations in which 3.0T-incompatible implanted medical devices or conditionally compatible 3.0T devices may result in significant susceptibility artifacts (secondary to local magnetic field inhomogeneity). Distortion related to these devices can easily degrade the quality of prostate MRI.10 A minimum standard prostate mpMRI, if protocoled carefully, can be used to detect lesions and be helpful for staging within its limitations.
2. Preferred/Ideal Standards
Some prostate mpMRI experts consider the ideal technique for tumor detection and staging to be the combination of 3.0T with endorectal and surface coils. ERC provides 5 times more SNR compared to surface coil and thus allows improved spatial resolution.13 Currently, the necessity of ERC at 3.0T remains uncertain; however, it is documented that the improvement in SNR can also improve the spatial resolution sufficiently so that minimal extraprostatic extension can be detected.14
Use of an ERC itself during image acquisition may not necessarily be enough to obtain an ideal prostate MRI. The current consensus is to use liquid barium or perfluorocarbon instead of air for coil insufflation, since air can induce susceptibility artifacts on diffusion weighted imaging (DWI).10 The ERC can result in patient discomfort and placement of an ERC requires an on-site physician. Although MRI using the ERC can provide more optimum lesion detection and staging, it is more time-consuming and costly.
B. mpMRI Parameters
Prostate MRI is usually termed “multi-parametric MRI” because it incorporates the combined use of anatomic and functional pulse sequences. Anatomic pulse sequences include T1 and T2 weighted (T1W and T2W) mpMRI. T1W mpMRI is not used for lesion detection; however, the purpose of its acquisition is to document biopsy related residual hemorrhage, which can mimic prostate cancer on mpMRI images. T1W mpMRI should be acquired in the axial plane using spin echo or gradient echo sequences; its acquisition is inherent for dynamic contrast-enhanced imaging. T2W mpMRI is the workhorse of mpMRI because the anatomic details can be best delineated on T2W mpMRI, mainly in the axial plane. T2W mpMRI should be acquired in two or three planes (sagittal, axial, and coronal) using fast/turbo spin echo sequences.
1. Basic parameters10
- Slice thickness: 3-4mm without gap
- Field of view (FOV): 12–20cm covering entire prostate and seminal vesicles
- In plane dimension:<0.7mm (phase) x <0.4mm (frequency)
Functional pulse sequences include diffusion weighted MRI (DW MRI) and dynamic contrast enhanced mpMRI (DCE MRI). Magnetic resonance spectroscopy is no longer recommended for clinical purposes, though may still be used in research settings. DW MRI evaluates the Brownian motion of water molecules within tissue, which is restricted in cancer-harboring tissues. DW MRI has two key components, apparent diffusion coefficient (ADC) maps and high b-value DW MRI. “b-value” is a factor related to the degree to which an acquisition is diffusion-weighted. Two or more b-values are needed to calculate ADC maps from DW MRI utilizing a mono-exponential decay model. ADC values extracted from maps are quantitative, however they are protocol- and platform-dependent and “intra-” and “inter-“patient variability can be significant for ADC values. Therefore, ADC maps are mostly used for qualitative interpretation. For ADC maps, if only two b‐values can be acquired due to time or scanner constraints, it is preferred that to obtain a low b-value at 50‐100 sec/mm2 and an intermediate b-value at 800‐1000 sec/mm2. Additional b‐values between 100 and 1000 may provide more accurate ADC calculations. A high b-value DW MRI of >1400 sec/mm2 should also be obtained, whether directly acquired or calculated from the lower b-values. The ADC map and the high b-value DW image are used in conjunction in a qualitative fashion.
2. Technical specifications of image acquisition for DW MRI10
- Echo time (TE): <90 msec; Repetition time (TR): >3,000 msec
- Slice thickness: <4 mm without gap
- FOV: 16–22 cm covering entire prostate and seminal vesicles
- In–plane dimension: <2.5 mm (phase and frequency)
DCE MRI evaluates the vascularity of the prostate in order to identify permeability changes related to tumor angiogenesis. DCE MRI consists of T1W gradient echo images obtained before, during and after injection of gadolinium-based contrast agents (GBCA).
3. Technical specifications of image acquisition for DCE MRI10
- TR/TE: <100 msec/<5msec
- Slice thickness: 3mm without gap
- FOV: 12–20 cm covering entire prostate and seminal vesicles
- In plane dimension: <2 mm (phase and frequency)
- Temporal resolution: <10 sec (<7 sec is preferred)
- Total scanning time: >2 min
- GBCA dose: 0.1 mmol/kg, injection rate: 2–3cc/sec
DCE MRI is the most invasive component of prostate MRI since it employs intravenous GBCA injection. The ACR provided updated guidance regarding concerns regarding the potential adverse event of nephrogenic systemic fibrosis (NSF), in its Manual on Contrast Media version 10.3 in 2018.15 Of note, class II agents (which include numerous macrocyclic agents, as well as the linear ionic agent gadobenate dimeglumine are preferred as there is an extremely low or possibly non-existent risk of NSF with these agents and checking of renal function before contrast administration is deemed optional with these agents. Further recommendations are given regarding monitoring of kidney function when using Class 1 and Class agents.
An additional concern related with GBCA is gadolinium accumulation in brain and bone tissues, as confirmed in autopsy series.16,17 One study with 9 participants reported that gadolinium deposition in normal brain and bone tissue occurred with macrocyclic and linear protein interacting agents in patients with normal renal function. In this study, deposition of gadolinium in cortical bone occurred at much higher levels compared with brain tissue.16 In another study with 15 participants, 5 of whom received GBCA injections, authors reported gadolinium deposition in neural tissues after GBCA administration in the absence of intracranial abnormalities that might affect the permeability of the blood-brain barrier.17 In addition to autopsy series, some studies also reported signal intensity changes at unenhanced MRI in deep brain structures in patients whom received GBCA injections. A meta-analysis of 25 publications, 19 of which were based on MRI analysis with a cumulative of 1247 patients found that signal intensity correlated positively with the exposure to GBCAs and was greater after serial administrations of linear nonionic agents compared with cyclic contrast agents. This meta-analysis revealed that the signal intensities were negatively correlated with the stability of GBCA. Despite such studies, there currently has been no proven harmful neurologic or physiological impact from gadolinium, and the clinical significance of gadolinium deposition remains unclear.18
4. Compliance with Current Guidelines
There is currently limited literature on compliance with technical standards of PI-RADS version 2 (PI-RADSv2) guidelines. In a study of prostate MRI scans from 107 different centers, Esses et al. evaluated variability in imaging facilities’ adherence to the minimum technical standards for prostate mpMRI acquisition established by PI-RADSv2.19 The study indicated that adherence to minimum standards was lowest on T2W mpMRI for frequency resolution <0.4 mm (16.8%) and phase resolution <0.7 mm (48.6%), lowest on DWI for FOV 120-220 mm (30.0%), and lowest on DCE MRI for slice thickness 3 mm (33.3%) and temporal resolution <10 s (31.5%). High b-value (>1400 s/mm2) DWI was included in 58.0% of exams, being calculated in 25.9%. Adherence to T2W mpMRI phase resolution and DWI inter-slice gap were greater (P < .05) at 3T than at 1.5T. Adherence did not differ (P > 0.05) for any parameter between examinations performed with and without an endorectal coil. Adherence was greater for examinations performed at teaching facilities for T2W mpMRI slice thickness and DCE MRI temporal resolution (P <0 .05).19 The overall findings of this study indicated that the compliance was variable; however, the impact of compliance on image quality and diagnostic accuracy was not explored.
5. Role of DCE MRI‐and Status of "Biparametric" MRI
One area of attention in prostate MRI is the relatively narrow role of DCE MRI within PI-RADSv2, largely being applied for characterization of indeterminate lesions (PI-RADSv2 category 3 lesions) in the peripheral zone (PZ). Upon release of PI-RADSv2, several subsequent studies evaluated the role of DCE MRI in prostate cancer diagnosis. Greer et al. evaluated the validity of the dominant sequence paradigm in a 58-patient retrospective nine reader study. Their results indicated that the probability of cancer detection for PI-RADSv2 category 2, 3, 4, and 5 lesions was 15.7%, 33.1%, 70.5%, and 90.7%, respectively. DWI outperformed T2W in the PZ (OR, 3.49 vs 2.45; P=0.008). T2W performed better but did not clearly outperform DW imaging in the transition zone (TZ) (OR, 4.79 vs 3.77; P=0.494). Lesions classified as PI-RADSv2 category 3 at DWI and as positive at DCE imaging in the PZ showed a higher probability of cancer detection than did DCE-negative PI-RADSv2 category 3 lesions (67.8% vs 40.0%, p=0.02). The addition of DCE imaging to DWI in the PZ was beneficial (OR, 2.0; P=0.027), with an increase in the probability of cancer detection of 15.7%, 16.0%, and 9.2% for PI-RADSv2 category 2, 3, and 4 lesions, respectively.20
In a study by Taghiour et al with 271 patients 209 of whom had PZ lesions, the role of DCE was investigated in equivocal lesions in the PZ. DCE was necessary to further classify (45/209) of patients who received a PI-RADSv2 score of 3 at DWI. DCE was positive in 29/45 cases, increasing the final PI-RADSv2 assessment category to a category 4, with 16/45 having a negative DCE. When compared with final pathology, DCE was correct in increasing the assessment category in 68.9% +7% (31/45) of cases with PI-RADSv2 score of 3 at DWI.21
Despite their retrospective nature, these studies revealed that DCE MRI has an important role in PI-RADSv2 for better cancer detection. However, some key studies, mainly from Europe, report that biparametric (T2- and diffusion-weighted imaging only) MRI (bpMRI) can be sufficient to detect clinically significant prostate cancer. In a brief analysis of bpMRI studies conducted in the era of PI-RADSv2, the majority of included studies reported high sensitivity of bpMRI within a range of 86 to 98% for detecting all or clinically significant prostate cancer, claiming equivalent performance to full MRI.22-27 Additionally, recent meta-analyses report a comparable sensitivity (74-79% vs. 76-79%) and specificity (88-90% vs. 89%) performances for bpMRI vs. mpMRI.28,29 It is possible that the performance of bpMRI may differ between highly refined research settings and more widespread clinical practice. Future research with larger scaled multi-institutional designs will help to clarify the actual diagnostic efficacy of bpMRI in prostate cancer care.
C. Reporting of Findings:
1. Reporting and PI–RADSv2
Current guidelines strongly encourage radiologists to use the PI-RADS v2 to report prostate mpMRI findings.10 This system is designed to evaluate treatment-naïve patients and aims to standardize the MRI interpretation. PI-RADSv2 defines criteria for scoring for each zone of the prostate on each pulse sequence. For T2W mpMRI and DW mpMRI, the score range is between 1 and 5, whereas for DCE mpMRI it is binary (positive or negative). For the PZ, the dominant sequence is DW mpMRI for scoring, whereas it is T2W MRI for the transition TZ. The role of DCE mpMRI for scoring is limited to indeterminate lesions with a score of 3 within the PZ. Once scoring for each lesion is completed for each pulse sequence, a final overall PI-RADSv2 score should be given for each lesion.
The overall score is between 1 to 5, which aims to predict likelihood of including clinically significant disease within the scored lesion: PI-RADS=1 (Very Low) suggests clinically significant cancer highly unlikely to be present, PI-RADS=2 (Low) suggests clinically significant cancer is unlikely to be present, PI-RADS=3 (Intermediate) suggests the presence of clinically significant cancer is equivocal, PI-RADS=4 (High) suggests clinically significant cancer is likely to be present, and PI-RADS=5 (Very High) suggests clinically significant cancer is highly likely to be present). This overall scoring is based on experts’ observations and is therefore qualitative; however, research related to this scoring system is ongoing in many centers.
Accurate interpretation of prostate mpMRI requires experience; however, its standards have not yet been clearly defined. One interesting point to note is that use of PI-RADSv2 can result in moderate agreement with reasonable sensitivity and tumor detection rates in early studies. Early studies evaluated the multi-reader agreement of PI-RADSv2 and accuracy. One study included 6 highly experienced uroradiologists from six different institutions to evaluate pre-determined lesions and score features of each lesion and assign a PI-RADSv2 score to test inter-observer agreement. PI-RADSv2 demonstrated modest reproducibility among six readers (κ=0.552). This study included a training session between reading sessions, which did not improve reproducibility. PI-RADSv2 seems to perform better in the TZ than previous versions with a κ=0.509 for the TZ and 0.593 for a PI-RADSv2 score ≥4. Additionally, agreement on DCE scores was low at κ=0.426. These findings indicate PI-RADSv2 does not suffer from lack of educational exposure, at least among experienced readers, and PI-RADSv2 represents a trend toward improved agreement for the TZ.30 Collectively, these early studies indicate PI-RADSv2 represents a major step forward in standardizing the acquisition and interpretation of MRI, but areas of uncertainty in the system remain, and improvements are necessary. The varying level of agreement and performance between readers of different experience suggests standardization between experience levels still needs to be addressed.
2. Marking and Processing of MRI for Reporting and Biopsy Purposes
In contemporary practice, prostate mpMRI is more commonly used for guiding biopsies rather than local staging. Accurate lesion mapping and dimension measurement are key steps in communication of the results to the referring physicians. PI-RADSv2 guidelines provide a sector map that divides the prostate into 12 sectors at apical, mid, and base levels. Detected lesions can be mapped on this sector map along with their estimated size. PI-RADSv2 recommends mapping of up to 4 suspicious lesions on this sector map. Such an approach can facilitate efficient communication of prostate mpMRI findings to referring physicians.10 Documentation of specific imaging series number and image number (e.g., Series 4, Image 15) of the index lesions, with those same lesions clearly annotated on the image, is crucial to the physician performing subsequent biopsies.
mpMRI guided biopsies can be performed using cognitive, transrectal ultrasound (TRUS)/mpMRI fusion or in-bore MRI guided approaches. Image processing in advance of the biopsy session is mandatory for TRUS/MRI fusion-guided approaches. This processing includes two important steps: 1) Segmentation of the prostate within axial T2W mpMRI, and 2) Labeling the target lesion within the prostate on axial T2W mpMRI. For segmentation of the prostate, manual, semi-automated or fully automated approaches can be used by radiologists or trained technologists under the supervision of radiologists. For labeling the index lesion, a radiologist should manually delineate intraprostatic target lesion(s) on axial T2W mpMRI using information from all pulse sequences. The application of the correct standards in image acquisition, interpretation and processing are critical to the successful use of mpMRI in this setting. Additionally, the collaboration and coordination between radiologists and urologists is also a key component. Radiologists should receive continuous feedback regarding segmentation quality and histopathology results of the target lesions that were segmented on mpMRI. Likewise, the urologist should receive feedback about the concordance of the imaging and biopsy findings, highlighting any potential issues related to image fusion/registration as well as possible targeting errors. Such an approach will further establish use of MRI in prostate cancer clinical care.
- Optimal scanning technique should utilize 3.0T surface coil; the need for an endorectal coil at 3.0T remains debated; an endorectal coil may be necessary for older 1.5T scanners; diagnostic quality prostate MRI has been reported without an endorectal coil using newer 1.5T systems.
- Identification and reporting of putative tumors uses anatomic and functional images. Image quality (especially avoiding air or stool in the rectum) and reader experience are paramount for accurate reporting.
- The radiographic report should identify up to 4 suspicious lesions with each individual lesion reported and characterized using PI-RAD v2 criteria.
Role of MRI in Screening for Prostate Cancer
The concept of screening a population for the purpose of finding a malignancy in its earliest stages of development, which could then allow selective, efficacious, and cost-effective treatment, is inherently attractive to patients and their physicians.
Population-based screening for prostate cancer has historically relied on prostate specific antigen (PSA) blood testing and digital rectal examination (DRE). Injudicious screening of populations unlikely to benefit from diagnosis, adherence to monolithic PSA “normal” values to guide recommendations for prostate biopsy, and poor decision making by patients and physicians regarding treatment of disease of low malignant potential lead to concerns about the value of PSA-based screening.
The conclusions of the U.S. Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (which originally reported no difference in prostate cancer mortality between screened and unscreened populations) have been called into question based on high contamination rates for PSA screening in the control arm of the study.31 The European Randomized Study of Screening for Prostate Cancer has shown an increasing absolute risk reduction in prostate cancer mortality with increasing length of follow-up.32 In response to these results the United States Preventive Services Task Force (USPSTF) has revised its negative recommendations regarding PSA screening.33 The current recommendation of the AUA is that men 55–69 years of age should discuss with their physicians the relative risks and harms associated with PSA-based screening.34
A recent study by Alpert evaluated the reduction in prostate cancer mortality for 400,887 patients undergoing routine PSA screening.35 When stratified for patient age and PSA testing interval, there was a 64% reduction in prostate cancer mortality for men 55–74 years of age and a 24% reduction in all-cause mortality. PSA-based population screening for prostate cancer is widely available, technically reproducible and relatively inexpensive. Multiple risk calculators, algorithms, and associated serum biomarkers may help mitigate the primary shortcomings of PSA screening (which are relatively limited specificity and sensitivity). Over-diagnosis and over-treatment are not shortcomings of PSA-based screening, they are the result of uncritical use of the information by physicians and patients. A summary statement based on a European consensus meeting at which 30 experts discussed the benefits, harms, and cost-effectiveness of prostate cancer screening noted that the participants “strongly agreed that PSA screening can substantially reduce prostate cancer mortality.” Furthermore, they concluded that “a limited screening program including active surveillance for men with low-risk tumors, can even be cost-saving”.36
mpMRI has been shown to have a beneficial role in risk stratification and repeat biopsy of the prostate. The use of mpMRI for population-based screening is intriguing. Because mpMRI costs approximately 10-20 times more than a PSA test and is associated with unquantified risks of gadolinium contrast administration, mpMRI-based screening would need to demonstrate superior performance characteristics to supplant existing PSA-based screening schemes.
Nam et al. recruited 47 men from the general population and performed a mpMRI as a primary screening test.37 The authors concluded that MRI had a 66.7% positive predictive value for patients with a normal PSA and a PI-RADS lesion >4 and a negative predictive value of 85.7% for patients with a PI-RADS lesion <3. The numbers were very small. In a follow-up article, Wallis et al. concede that cost is a major impediment to the adoption of mpMRI-based screening.38 They suggest that the cost can be offset by reducing the number of biopsies performed if the MRI is “negative”.
There are several significant impediments to the adoption of mpMRI as a stand-alone, population-based screening strategy:
- The quality of mpMRI images is highly dependent on equipment and scanning protocols. The interpretation of images and assessment of risk based on those images is subjective and demonstrates poor inter-reader reproducibility despite attempts to standardize reading using PI-RADSv2.39
- mpMRI may miss 35% of clinically significant prostate lesions when the standard is comparison to whole-mount pathology specimens.40 This deficiency is acknowledged by the inclusion of standard biopsy in nearly every major series promoting mpMRI directed fusion biopsy.
- The cost of mpMRI is not supportable as a generalized stand-alone screening strategy. Barnett et al. found a potential cost-effectiveness benefit to incorporating mpMRI in a risk-stratification protocol for biopsy but only in a population pre-stratified by PSA testing.41 There is some evidence that bpMRI may perform as well as mpMRI.42 If MRI can be performed without contrast, in less time and for a lower cost, it could become viable for generalized stand-alone screening.
- Current evidence does not support the use of mpMRI for stand-alone, population-based screening for prostate cancer.
Initial Evaluation of Biopsy-Naïve Patients Suspected of having Prostate Cancer
A. Pre–Biopsy Risk Stratification
Standard TRUS-directed biopsies and appropriate selection criteria yield positive biopsy rates that may be as high as 60%, with only 20%–25% of patients diagnosed by that modality having low-stage, low-grade disease. More restrictive selection criteria for biopsy will result in increased diagnosis of clinically significant cancers and decreased diagnosis of low-volume, low-stage disease, independent of the imaging modality used.
As an increasingly useful tool for prostate cancer, detection, and risk stratification, mpMRI allows noninvasive assessment of the prostate gland from both an anatomic and a functional perspective. A recent meta-analysis demonstrated sensitivity ranging from 44% to 87% for the detection of clinically significant prostate cancer and negative predictive value (NPV) ranging from 63%–98% for exclusion of clinically significant prostate cancer.43 The use of mpMRI in clinical practice is critically dependent upon the availability of high quality mpMRI interpreted by radiologists experienced in the technique.
Because the selection criteria for mpMRI and biopsy vary widely within the published literature, stratification by mpMRI suspicion score allows better determination of the reproducibility of mpMRI-targeted biopsy in cancer detection. The MRI score has been shown to be the single most important determinant of prostate cancer risk. In a prospective study of 1,042 men who underwent mpMRI followed by MRI or ultrasound fusion biopsy, lesion suspicion score was the most powerful predictor of clinically significant cancer detection (odd ratio = 6.5, P<0.01).44 The PI-RADSv2 scoring system corresponds with the detection of prostate cancer and clinically significant disease as the suspicion score increases. Based on targeted biopsy on a per lesion basis, the overall cancer detection rates of PI-RADSv2 2, 3, 4 and 5 scores for all tumors ranges from 0%–22%, 10%–16%, 30%–77% and 78%–89%, respectively.45,46 The cancer detection rate of PI-RADSv2 2, 3, 4, and 5 scores for Gleason >7 has been reported to be 5%–6%, 0%–14%, 21%–78% and 75%–100%, respectively.47,48
mpMRI has been reported to predict more aggressive disease including a positive correlation of mpMRI findings with D’Amico risk scores.49 Moreover, individual MRI sequences such as ADC maps derived from DWI and quantitative parameters of DCE have been reported to predict tumor aggressiveness in a noninvasive manner. ADC values derived from DWI images are inversely correlated with the Gleason score of lesions at biopsy or surgery and may further influence risk stratification, however the confidence intervals are widely overlapping, limiting the ability to use ADC as a surrogate of Gleason score.50 ADC measurements have been shown to improve accuracy in discriminating Gleason score 3+4=7 from Gleason score 4+3=7 tumors.22 Decreasing ADC values may represent a strong risk factor of harboring a poorly differentiated prostate cancer, independent of biopsy characteristics. ADC predicts time to treatment, time to adverse histology, is an independent predictor of progression on AS, predicts BCR after radical prostatectomy, as well as RT and brachytherapy.51-56 Furthermore, ADC may have potential for predicting extracapsular extension (ECE) as well as seminal vesicle invasion (SVI) before surgery in patients with prostate cancer, thus improving preoperative staging.57-59
In an attempt to improve on the current limitations of prostate cancer screening, risk calculators using multivariable mathematical models and nomograms predicting overall cancer detection as well as clinically significant prostate cancer have been developed.60-61 Employing mpMRI may assist in the decision as to whether a man needs a prostate biopsy and has been incorporated into several decision-making models. In a study of 175 men, Salami et al. demonstrated mpMRI outperforms the Prostate Cancer Prevention Trial risk calculator in predicting clinically significant prostate cancer, and its application may help select patients who will benefit from diagnosis and treatment.62 Nomograms have been developed for the pre-biopsy setting predicting the risk of both overall and Gleason score >7 cancer on both mpMRI-ultrasound fusion and systematic biopsy with a high degree of accuracy by incorporating the MRI suspicion score, PSA density, and age.63 Employing these nomograms may help determine the necessity for biopsy in a wide variety of clinical scenarios. For example, utilizing the nomograms of Bjurlin et al., a 75-year-old man with a PSA of 6.2, prostate volume of 45 cm3 (PSA density 0.14 ng/ml-cc), and a low MRI suspicion score has a 28% chance of harboring prostate cancer, but less than a 5% chance of Gleason score >7 prostate cancer and he may choose to defer a biopsy.63 Conversely, a 55 year-old man with the same PSA level, prostate volume, and MRI finding may choose to undergo a biopsy given the natural history of prostate cancer in a man his age. Predictive models incorporating MRI findings provide important information for physicians and patients in assessing an individual’s risk for prostate cancer. The use of risk assessment tools identifies those men who may benefit most from a biopsy. The accurate assessment of the risk of harboring clinically significant disease allows for individualized patient counseling.
- MRI suspicion score correlates well with the likelihood of clinically significant cancer, potentially allowing pre-biopsy risk stratification for individualized decision-making.
- Clinically, MRI-suspicion scores (based on ADC value and diffusion weight imaging) correlate with the risk of adverse pathology on radical prostatectomy, risk of biochemical relapse following surgery, and the likelihood of progression on active surveillance.
- The implementation of mpMRI-based risk stratification in clinical practice, particularly in guiding clinical decision-making, is predicated upon the availability of high quality mpMRI and experienced readers.
- Data derived from pre-biopsy mpMRI can enhance the predictive ability and overall diagnostic accuracy of currently available clinical prediction tools.
B. Evaluation of Biopsy–Naïve Patients Utilizing mpMRI
In men presenting for a first prostate biopsy, the potential advantages of mpMRI and targeted biopsy are twofold: improving detection of high-grade cancer and avoiding detection of low-grade disease by selectively targeting tumor foci that are more likely to be clinically significant. The performance characteristics of mpMRI targeted biopsy vary with the clinical indication, in part, due the variable prevalence of disease in the study cohort. As such, the absolute rates of detection, when not stratified by suspicion score, may vary between series, but trends remain similar.
Randomized clinical trial evidence supports the use of MRI in men at risk for prostate cancer presenting for first prostate biopsy. PROMIS was a multicenter, paired-cohort, confirmatory study to compare the diagnostic accuracy of mpMRI and TRUS-guided systematic biopsy against a reference template prostate mapping biopsy.64 Of the 576 men who underwent both TRUS biopsy and mapping biopsy, MRI was more sensitive for clinically significant cancer (defined as GS >4+3) than TRUS biopsy (93% vs 48%) and less specific (41% vs 96%). The authors concluded that using mpMRI to triage men might allow 27% of patients to avoid a primary biopsy, and the diagnosis of 5% fewer clinically insignificant cancers. If subsequent TRUS-biopsies were directed by mpMRI findings, up to 18% more cases of clinically significant cancer might be detected compared with the standard pathway of TRUS-biopsy.64 Importantly, the authors reported a NPV of 89% for low suspicion MRI, but when the definition of clinical significance was broadened to the more commonly utilized metric of Gleason 3+4, the NPV decreased to 74%. It is important to note that while MRI identified 93% of clinically significant cancers by the study definition, it cannot be assumed that all such cancers would have been identified on MRI-targeted biopsy.
The PRECISION trial was a multicenter randomized, noninferiority trial, assigning men with a clinical suspicion of prostate cancer who had not undergone biopsy previously to undergo mpMRI, with or without targeted biopsy, or standard TRUS biopsy.65 Men with low suspicion mpMRI (PI–RADS 1–2) did not undergo biopsy. A total of 500 men underwent randomization. In the mpMRI–targeted biopsy group, 71 of 252 men (28%) had mpMRI results that were not suggestive of prostate cancer; consequently they did not undergo biopsy. Clinically significant cancer (defined as >Gleason 3+4) was detected in 95 men (38%) in the mpMRI-targeted biopsy group, as compared with 64 of 248 (26%) in the standard-biopsy group (P=0.005).65 mpMRI as a risk assessment tool prior to initial biopsy and mpMRI–targeted biopsy was found to be not only non-inferior, but superior to standard TRUS-biopsy for the detection of clinically significant cancer, and fewer men undergoing mpMRI–targeted biopsy were found to have indolent (Gleason 3+3) cancers. The study has been criticized in that systematic biopsy was not performed in the mpMRI–targeted biopsy arm, and, as such, the number of clinically significant cancers missed outside the targeted region, or among men with PI–RADS 1–2 mpMRI is not defined. Nonetheless, as a result of these 2 studies, the UK National Institute for Health and Care Excellence recommends prostate mpMRI as a first line investigation in men with suspected clinically localized prostate cancer.66
The MRI–FIRST trial was a prospective, multicenter, paired diagnostic study, conducted at 16 centers in France to address whether mpMRI before biopsy would improve detection of clinically significant prostate cancer in biopsy-naive patients.67 All patients underwent TRUS guided systematic and hypoechoic directed biopsies, followed by 2 cores of MRI targets in those with mpMRI regions of interest (Likert 3,4,5). A total of 275 patients were enrolled, 24 (9%) were excluded from the analysis and 53 (21%) of 251 analyzed patients had negative (Likert <2) mpMRI. Detection of clinically significant disease by systematic biopsy (30%) and targeted biopsy (32%) did not differ significantly (P=0.38), but was highest when both techniques were combined. The authors did not discuss the outcome of reduction of indolent disease detection in their study analysis, but it is noteworthy that 49/56 (87.5%) of non-significant cancer was found on systematic biopsy and only 14/56 (25%) on targeted sampling, suggesting that 75% of indolent cancers were identified by systematic biopsy alone. These data are consistent with prior studies and would suggest that maintaining systematic biopsy will increase the risk of continued over-diagnosis of indolent disease while allowing a low, but consistent rate of clinically significant cancer detection.59,68-70
These studies taken together, provide strong evidence regarding the benefit of pre-biopsy mpMRI among men with no previous biopsy, but leave questions regarding whether it is safe to avoid a biopsy in men at risk for prostate cancer with a low risk mpMRI (PI-RADS regions of interest <2). Individual institutional experience with mpMRI and an active quality assurance program assessing mpMRI-targeted biopsy outcomes is necessary to decide on the validity of this approach as a learning curve for both MRI and biopsy has been shown.71,72
The oncologic relevance of high-grade tumors missed on mpMRI are not yet entirely characterized.73 The cost and feasibility of performing large volume mpMRIs must be considered. Cost effectiveness studies appear to suggest the downstream benefit of biopsy reduction or avoidance and increased quality adjusted life years through the adoption of an mpMRI and mpMRI-targeted biopsy care pathway.74-76 Additional risk stratification tools such as biomarkers, PSA velocity, family history, and age may be incorporated into the diagnostic pathway.77
- Two randomized clinical trials have provided level 1 data to support the recommendation of mpMRI prior to biopsy for all men, without previous history of biopsy, under consideration for prostate biopsy.
- mpMRI-targeted prostate biopsy in men at suspicion of prostate cancer, with no previous history of prostate cancer, detects more clinically significant prostate cancer when combined with systematic biopsy, and less clinically insignificant prostate cancer, than systematic biopsy alone.
- The use of mpMRI-targeted biopsy alone in men at suspicion of prostate cancer with no previous history of biopsy risks missing a small number of clinically significant cancers identified by systematic biopsy alone. Therefore, use of systematic biopsy in conjunction with mpMRI-targeted sampling is advisable until the time that individual experience demonstrates a low risk of missed clinically significant cancers. Continued use of systematic biopsy will increase the risk of over-detection.
- In considering the use of pre-biopsy MRI, quality, experience of the interpreting radiologist, cost, and availability of alternate biomarkers should be considered.
C. Evaluation of Men with Previsou Negative Biopsy by mpMRI
Among men with persistent suspicion of prostate cancer despite previous negative biopsy, the rationale for pre-biopsy mpMRI is the potential for detection of occult cancers missed by previous systematic sampling. These cancers are often located in the anterior TZ or fibromuscular stroma, the extreme apex, or base, and would likely be missed by routine systematic sampling. Historically, serial biopsy series have demonstrated a declining rate of cancer detection with each biopsy. For example, Roehl et al. noted a cancer detection rate of 29%, 17%, 14%, 11%, 9% and 7% respectively on serial repeat systematic biopsy, and Sonn et al. reported no change in significant cancer detection rate (GS≥7 or CCL>4 mm) among men with 1, 2, 3, or >4 negative biopsies (range, 23%–29%).78–80
The rate of cancer detection on repeat biopsy when incorporating mpMRI-targeted cores has varied from 11%–54%, while the rate of clinically significant cancer detection has varied from 10%–40%, likely due to variation in patient selection, mpMRI technique, and biopsy technique. Several series have demonstrated increased high-grade cancer detection by mpMRI-targeted biopsy, when compared to systematic biopsy, among men with one or more prior negative systematic biopsies. Sonn et al, for example, observed that targeted biopsy detected more clinically significant cancers and fewer clinically insignificant cancers than systematic biopsy.80
In addition to increased cancer detection, other authors have noted that systematic biopsy contributes relatively little in the detection of clinically significant cancer in this cohort. Among 140 men, Salami et al. similarly observed that targeted biopsy detected more clinically significant cancer than systematic biopsy (48% vs 31% of total cohort), and that mpMRI-targeted biopsy missed only 3.5% of clinically significant cancers found uniquely on systematic biopsy.62 Mendhiratta, et al, evaluated 172 men undergoing repeat biopsy by combined mpMRI-TRUS fusion targeting and systematic sampling. While systematic biopsy was negative in 14/31 (48%) men with Gleason >≥7 cancer noted on MRI-targeted sampling, MRI-targeted biopsy missed no high-grade cancers.70
Additionally, in each of these studies, the pre-biopsy suspicion score strongly predicted the likelihood of high-grade cancer on biopsy. In the study by Mendhiratta, et al., a pre-biopsy mpMRI suspicion score of < 4 carried negative predictive values of 95% and 100% for the detection of Gleason 3+4 and Gleason > 4+3 disease, respectively.73
A consensus statement of the American Urological Association and the Society of Abdominal Radiology's Prostate Cancer Disease-Focused Panel highlights several strategies to increase optimization in the previous negative biopsy setting.81 First, MRI must be of high quality and should be performed, interpreted, and reported in accordance with PI-RADS guidelines. Second, experience by the reporting radiologist and biopsy operator are required to achieve optimal results and practices integrating prostate mpMRI into patient management are advised to implement quality assurance programs to monitor targeted biopsy results. Third, patients receiving a PI-RADS assessment category of 3-5 warrant repeat biopsy with image guided targeting. Fourth, at least two targeted cores should be obtained from each mpMRI-defined target. Fifth, a case-specific decision must be made whether to also perform concurrent systematic sampling in addition to targeted biopsy. Sixth, performing solely targeted biopsy should only be considered once quality assurance efforts have validated the performance of prostate mpMRI interpretations with results consistent with the published literature. Lastly, in men with low risk mpMRI, (PI-RADS<2), ancillary markers may be of value to identify patients warranting repeat systematic biopsy. Series that have incorporated mpMRI-targeted sampling in their repeat biopsy scheme have consistently demonstrated increased cancer detection relative to systematic sampling, unique cancer detection among MRI-targeted cores, and consistent cancer detection rate, regardless of number of previous biopsy sessions. mpMRI and mpMRI-targeted biopsy is endorsed by the National Comprehensive Cancer Network guidelines in men with a prior negative biopsy at risk for harboring occult disease in order to maximize the detection of higher-risk disease and limit the detection of lower risk disease.82
- The use of mpMRI is in men with a rising serum PSA level for whom there is a suspicion for prostate cancer despite a previous negative prostate biopsy is now endorsed by the National Comprehensive Cancer Network guidelines and the joint consensus statement of the American Urological Association and the Society of Abdominal Radiology which states:
- When high-quality prostate mpMRI is available, it should be strongly considered in any patient with a prior negative biopsy who has persistent clinical suspicion for prostate cancer and who is undergoing a repeat biopsy.
- The decision whether to perform mpMRI in this setting must also take into account results of any other biomarkers, the cost of the examination, as well as availability of high-quality prostate mpMRI interpretation.
- Patients receiving a PI-RADSv2 assessment category of 3-5 warrant repeat biopsy with image guided targeting.
- TRUS-mpMRI fusion or in-bore mpMRI-targeting may be valuable for more reliable targeting, especially for lesions that are small or in difficult locations. However, in the absence of such targeting technologies, cognitive (visual) targeting remains a reasonable approach in skilled hands.
- Performing solely targeted biopsy should only be considered once quality assurance efforts have validated the performance of prostate mpMRI interpretations with results consistent with the published literature.
- In patients with a negative or low-suspicion mpMRI (PI-RADSv2 assessment category of 1 or 2, respectively), other ancillary tests (i.e., PSA, PSA density, PSA velocity, prostate cancer antigen 3 [PCA3], Prostate Health Index [PHI]) may be of value to identify patients warranting repeat systematic biopsy, although further data is needed on this topic.
- If a repeat biopsy is deferred on the basis of the MRI findings, then continued clinical and laboratory follow-up is advised and consideration should be given to incorporating repeat MRI in this diagnostic surveillance regimen.
Staging and Treatment Planning for Prostate Cancer
A. Role of mpMRI in staging prostate cancer
Before being studied for localizing prostate cancer and guiding biopsies, mpMRI was used for staging.83 mpMRI has utility for assessing the presence/absence of significant cancer, prediction of organ-confined disease (OC), prediction of extraprostatic (EPE)/extracapsular extension (ECE) of cancer, and assessment of SVI. Note: although EPE is often considered the preferred terminology for extraprostatic extension of prostate cancer due to the lack of a true capsule on the prostate, others use ECE; due to this, EPE and ECE may be used interchangeably]. When mpMRI is performed at a center of excellence, adding MRI imaging to standard clinical nomograms provides significantly improved ability to predict adverse pathology at time of radical prostatectomy, as the AUC increased by 0.10 for prediction of organ-confined disease, 0.10 for ECE, and 0.09 for seminal vesicle invasion.84 However, it is essential to understand there are significant limitations in predicting extraprostatic disease, particularly for microscopic ECE, SVI, or lymph node involvement.
1. Use in Detecting Clinically Significant Disease
When determining the utility of mpMRI in the diagnosis and staging of cancer, mpMRI images are compared to final surgical pathology at radical prostatectomy. Turkbey et al. studied 45 patients and found a 98% PPV of mpMRI in identifying any cancer within the prostate on final pathology.85 Sensitivity of detection was higher for lesions >5 mm in size and with Gleason score >7 (Grade Group 4-5). Similarly, in 122 men who underwent mpMRI before radical prostatectomy, Le showed a 72% overall sensitivity for detecting tumors with Gleason score > 7 (Grade Group 3-5)or tumors > 1 cm.86 Of the tumors missed on mpMRI, 75% were Gleason 6 (Grade Group 1) while only 4% were Gleason > 8 (Grade Group 4-5). Baco et al showed a 95% concordance between the index tumor location on biopsy and final pathology and Delongchamps showed mpMRI underdetected only 4% of patients with significant cancer and the index tumor was missed in only 1 of 125 patients.87,88 Lim et al showed patients with Gleason 3+4=7 on biopsy, a higher PRADS score correlated with higher risk of upstaging to Gleason 4+3 disease.89
2. Use in Predicting Organ Confined Disease
mpMRI has also been shown to provide improved risk assessment over prior diagnostic tools such as nomograms. Gupta et al. showed mpMRI was more accurate in predicting organ confined (OC) disease on pathological analysis than Partin tables in 60 men who underwent radical prostatectomy. The sensitivity, specificity, PPV, and NPV of mpMRI in predicting OC disease were 82%, 86%, 91%, and 73%, respectively.90 In a second study of 158 men, Gupta et al. again showed radiologic staging using mpMRI was more accurate in predicting organ confined disease (AUC 0.88) than the Partin tables (AUC 0.70). In this study, predicting organ confined disease was improved when mpMRI was combined with PSA (AUC, 0.91).91
3. Use in Predicting Extracapsular (Extraprostatic) Extension
mpMRI has reasonably high sensitivity, specificity, PPV, and accuracy in predicting ECE at the time of radical prostatectomy (Table 1), although is less accurate in finding focal ECE. The clinical utility in changing patient outcomes from this information has yet to be established.
Somford et al. showed an overall accuracy of 74% of preoperative mpMRI to detect ECE on final pathology in 183 men undergoing radical prostatectomy. On multivariate analysis, only PSA and stage on mpMRI were associated with ECE, with mpMRI being the strongest predictor.14 Gupta showed mpMRI had a sensitivity, specificity, PPV, and NPV in detecting ECE of 78%, 83%, 67%, and 90%.90 Raskolnikov et al. similarly showed a sensitivity, specificity, and PPV and NPV for ECE to be 49%, 74%, 36% and 83%, respectively, in 169 patients, but showed mpMRI was not reliably able to identify microfocal ECE. On multivariate regression analysis, only patient age and mpMRI/TRUS fusion guided biopsy Gleason score were independent predictors of ECE on final pathology.92 In 87 patients with clinically localized prostate cancer with a pre-operative mpMRI who underwent a radical prostatectomy (of which 31 had ECE), Boesen et al. showed a sensitivity and specificity of 81% and 78% for ECE by mpMRI.93 Feng et al. showed mpMRI could predict ECE in all zones, independent of PSA, Gleason score, and clinical stage but was least sensitive at the apex, and was less accurate for focal ECE. Overall, sensitivity, specificity, PPV and NPV of mpMRI for ECE were 71%, 91%, 57%, and 95%, respectively.94
Schieda et al. showed the importance of using a standardized scoring system such as PI-RADS when evaluating for ECE. When using PI-RADS compared to non-standardized reporting (in 65 and 80 patients, respectively), PI-RADS scoring had a 60% sensitivity, 68% specificity, and 63% accuracy for ECE, which was more uniform across readers, compared to 24% sensitivity, 75% specificity, and 42% accuracy for non PI-RADS scoring.95
Although MRI is useful for predicting the likelihood of ECE, it should not categorically be used as the sole indicator of nerve-sparing or surgical planning.
Table 1: Sensitivity, specificity, PPV, NVP, and accuracy in predicting ECE on mpMRI
|Rasholnikov92||48.7||73.9||35.9||82.8||Not reliable for micro–focal disease|
|Feng94||70.7||90.6||57.1||95.1||Lowest sensitivity at apex, less accurate for focal ECE|
4. Use in Predicting Seminal Vesicle Invasion
Preoperative identification of SVI of prostate cancer can have important implications in treatment recommendations and surgical planning. mpMRI has a high sensitivity and specificity for seminal vesicle invasion. Soylu et al. showed specificity of 96% to 98% and a PPV of 70% to 79% for mpMRI correctly identified seminal vesicle invasion in 131 men.96 Another study found targeted biopsy detected cancer in 71% of 28 lesions in the seminal vesicles with moderate to high suspicion for malignancy on mpMRI.97 In a study of 54 men with SVI at surgery (among 527), combination of clinical factors and mpMRI findings led to the highest accuracy. mpMRI alone had sensitivity of 76%, specificity 95%, PPV of 62%, and NPV of 97%.98
B. Role of mpMRI in Selecting Therapy – Local Management, Surgical Choice, and Technique
Identification of pathologic features of cancer is important to help guide therapy in individual patients. Results from mpMRI can be integrated into currently available clinical staging systems, and the information can be extrapolated to help risk stratify patients, guide therapy choice, and inform surgical technique. Therapeutic technique including surgical technique, radiation planning, and antihormonal therapy may be modified based upon the improved accuracy of radiologic staging over clinical staging.
1. Radical Prostatectomy Planning
mpMRI has been shown to be helpful to surgeons in pre-operative planning, although it has yet to be proven to lead to improved patient outcomes. Among 438 men undergoing prostatectomy from 2009-2012 randomized to MRI vs non-MRI, there were no differences in positive surgical margin rates between the two groups.99 Park et al. studied 353 men who underwent radical prostatectomy with a pre-operative mpMRI where the surgeon determined preoperatively the degree of nerve sparing (bilateral, unilateral, none) they would use without incorporating the mpMRI findings, and then once again after reviewing the MRI. The surgical plan was changed in 26% of the patients, to either a more aggressive nerve sparing approach (57%) or a wider margin of resection (43%). In patients with intermediate and high risk features, a change was made in 83% and 89%, respectively.100 Similarly, McClure et al. showed the surgeon changed their initial surgical plan in 28 of 104 (27%) patients after reviewing the MRI.101 The surgical plan was changed to a nerve-sparing technique in 17 of the 28 patients (61%) and to a non-nerve-sparing technique in 11 (39%). Seven of the 104 patients (6.7%) had positive surgical margins. In patients whose surgical plan was changed to a nerve-sparing technique, there were no positive margins on the side of the prostate with a change in treatment plan.101 There is no direct evidence that changing the surgical plan resulted in a difference in margin status in any patient.
2. Radiation Therapy Planning and Androgen Deprivation Therapy (ADT) Duration
Accurate radiological staging is important for target volume definition and dose prescription in conformal radiotherapy when treating prostate cancer. Kamrava et al. showed 12% (21 of 183) of patients were stratified into a higher risk category using an mpMRI/TRUS fusion biopsy, and 18% were upgraded to intermediate or high risk from the low risk group.102 Panje et al. studied 122 patients who underwent radiation therapy and found tumor stage shift occurred in 56% of patients after mpMRI. Upstaging was most prominent in patients showing high PSA (>20 ng/dL) (73%) but was also substantial in patients presenting with low-risk PSA levels (< 10ng/dL) (50%) and low-risk Gleason scores (45.2%). Risk group changes occurred in 29% with consequent treatment adaptations regarding target volume delineation and duration of androgen deprivation therapy.103
Muralidhar et al. studied the Surveillance, Epidemiology, and End Results (SEER) database and identified 60,165 men who underwent radical prostatectomy and noted their clinical and pathologic features and their 10-year prostate cancer-specific mortality (PCSM). Patients clinical stage T1/T2 with T3a following prostatectomy had less than half the risk of PCSM as those with clinical T3 disease prior to surgery, and a subset of those men had similar risk as patients with pathologic T2 disease. Therefore, they extrapolated that radiation-managed patients with low-grade/intermediate-grade T3a disease by mpMRI may only need short-term ADT, but those with T3b or high-grade occult T3a disease (who have similar PCSM as those presenting with cT3 disease) should be treated aggressively, including long-course ADT when managed by radiation.104
3. Use of mpMRI for Focal Therapy Planning
The addition of mpMRI and mpMRI-fusion biopsies has been studied in regard to patient selection for focal therapy. The results have been mixed. Lee MS et al. found a one-to-one correlation with radical prostatectomy specimens that MRI had an NPV of 46% so missed a high number of clinically significant lesions, but its PPV of 97% makes it a potentially useful tool for planning focal therapy.105 When comparing final pathology results from prostatectomy specimens to preoperative biopsies in patients with intermediate risk disease on MRI fusion biopsy who are potentially eligible for focal therapy Nassiri et al. showed combined targeted and template biopsy, had 80% sensitivity, 74% specificity, and 75% accuracy for focal therapy eligibility whereas targeted cores alone yielded 73% sensitivity, 48% specificity and 55% accuracy. In a retrospective analysis of 217 patients who met biopsy criteria for focal therapy (unilateral tumor, clinical tumor stage <cT2a, prostate volume &ly;60 mL and either biopsy Gleason 3 + 3 or < 3 + 4 and PSA <10 or <15 ng/mL) and 113 who met criteria based upon biopsy and MRI.106 Pompe et al. showed only 30% and 33%, respectively remained eligible for FT according to final histopathological results, based on their criteria. Sensitivity, specificity, PPV and NPV for MRI to predict contralateral tumor were: 41.8, 71.6, 70.9 and 42.6%, respectively.107
There are also concerns mpMRI typically underestimates tumor volume. A comparison of mpMRI and post-prostatectomy histology for 46 individual cancers found that mpMRI underestimated volume by average of 18%; underestimation was more notable in lesions with higher PI-RADS scores and higher Gleason scores.108 Among 118 cancer foci evaluated between mpMRI and whole-mount histology, median distance a tumor extended beyond the mpMRI contour was 13 mm and ~80% of cancer volume was outside the MRI region-of-interest.109 Among 40 index lesions in 40 men, T2, DWI, and DCE underestimated tumor volume by means of 55%, 58%, and 18%, respectively.110 For focal therapy, DCE images may be the most accurate for estimating tumor volume.
In summary, although, MRI improves overall accuracy for patient selection for focal therapy, it cannot safely exclude or minimize chance of significant cancer elsewhere or on the contralateral prostate side, and therefore further studies and models are needed to help select patients for focal therapy.
C. Role of mpMRI in Evaluating Regional Lymphatics
Currently available imaging modalities for the evaluation of lymph nodes in patients with intermediate to high risk prostate cancer have high specificity and accuracy but only low to moderate sensitivity. mpMRI appears to be equivalent to computerized tomography (CT) and positron emission tomography (PET) in this regard.
Although we are not aware of any contemporary direct comparisons of CT and mpMRI for pelvic lymph node metastases, a meta-analysis published in 2008 suggested no meaningful difference in operating characteristics, although both were notably suboptimal with pooled sensitivity of 0.39 – 0.42 and pooled specificity of 0.82.111
Nearly all contemporary comparisons involve mpMRI versus PET/CT. Heck et al. prospectively compared CT, DWI mpMRI and [11C]choline PET/CT in 33 intermediate- and high-risk prostate cancer patients who then underwent radical prostatectomy with extended lymph node dissection. Metastases were detected in 14 of 33 (42%) patients and in 92 of 1,012 (9%) lymph nodes. All three imaging techniques exhibit a low sensitivity with less than two-thirds of lymph node metastases being detected. Overall diagnostic efficacy did not differ significantly between imaging techniques.112 Van den Bergh et al. compared PET-CT to DWI mpMRI in 75 patients at high risk for lymph node metastasis (10%–35% risk based upon Partin tables) and showed mpMRI does not add value in the evaluation of lymph nodes in patients with a negative PET-CT.113 There was low sensitivity of (8.2% and 9.5%) and a positive predictive value (PPV) of 50.0% and 40.0% for both C-choline PET-CT and DW mpMRI, respectively. Even when both imaging modalities were combined, sensitivity values remained too low to be clinically useful.113 Pasoglou et al. evaluated 30 consecutive patients with high risk prostate cancer and showed that a combination of mpMRI with concomitant whole body mpMRI had a higher sensitivity (100% vs. 85%) and higher specificity (100% vs. 88%) for metastasis (bone and lymph nodes combined) when compared to bone scan with X-ray and CT scan.114
Von Below et al. showed that mpMRI DWI had a 90% specificity, 55% sensitivity, and 72.5% accuracy for lymph node metastasis in 40 patients with intermediate- and high-risk prostate cancer, 20 of whom had histologically-proven lymph node positive disease. The true-positive patients had significantly more involved lymph nodes (mean 6.9 versus 2.7), with larger diameter (mean 12.3 versus 5.2 mm) compared with the false-negative group.115 Vallini et al. showed that using 3.0T DWI mpMRI with a multiple b-value spin echo-echo planar imaging (SE-EPI) sequence may help distinguish benign from malignant pelvic lymph nodes in patients with prostate cancer.116
- Staging patients with prostate cancer using MRI to evaluate possible lymph node metastasis can be considered in selected patients (T3/T4 and T1/T2 patients with nomograms predicting the risk of lymph node metastasis >10%.
- mpMRI/TRUS may offer valuable staging information when performed prior to definitive local therapy. However, the current staging accuracy has not demonstrated the capability to rule out microscopic capsular extension or positive margins.
D. Evaluation for Local Recurence
mpMRI can be of value in men with biochemical failure after radical prostatectomy and radiation therapy, to help evaluate for local recurrence versus systemic recurrence, to help guide biopsies, and to help inform therapy choice. Suspicion of recurrence in the setting of biochemical failure is a valid reason for clinicians to request a mpMRI.
After radical prostatectomy, mpMRI is a useful tool because there is both a functional component and anatomic component to the test, the combination can be used to help differentiate among local recurrence of tumor, normal residual prostate tissue, or scar or fibrosis with granulation tissue.117 mpMRI should be able to differentiate fibrosis and atrophic remnant seminal vesicles after prostatectomy from local relapse. DCE imaging appears to be the most sensitive sequence to detect local recurrence, but DWI could be substituted as a reasonable alternative without compromising diagnostic accuracy.118 Linder et al. identified 187 men who underwent endorectal coil MRI with dynamic gadolinium-contrast enhancement followed by TRUS- guided prostatic fossa biopsy; local recurrence was identified in 132 patients, with 124 (94%) detected on e-coil MRI. The median PSA was 0.59 ng/mL (range < 0.1–13.1), and median lesion size on MRI was 1 cm. Sensitivity, specificity, PPV and NPV was 91%, 45%, 85% and 60% respectively.119 Since current evidence suggests that for salvage radiation therapy, lower pre-radiation PSA levels correspond to more durable responses, it is important to note that even in patients with a low PSA (< 0.4 ng/mL) the sensitivity was 86%.120 When a lesion was identified on mpMRI, the positive biopsy rate was 65%, and positive biopsy rates were 51% if the lesion was < 1 cm, 74% if 1 cm – 2 cm, and 88% if > 2 cm.119
mpMRI can also be used to help targeted biopsies to more accurately diagnose radiation failure and to possibly determine who may benefit more from local and even focal salvage therapy.121 Diagnostic accuracy in the identification of tumors is better with a multi-parametric approach over strictly T2WI or DCE. Brachytherapy, external beam radiotherapy, and focal therapies tend to diffusely decrease the signal intensity of the peripheral zone on T2-weighted images due to the loss of water content, consequently mimicking tumor and hemorrhage. The combination of T2WI and functional studies such as DWI and DCE imaging improves the identification of local relapse. Tumor recurrence tends to restrict on diffusion images and avidly enhances after contrast administration.118
In an assessment of 10 patients, Muller et al. found that all 10 had positive findings suspicious for local recurrence on mpMRI per entrance criterion. MRI-TRUS biopsies were positive in 10/16 lesions (62.5%) and 8/10 (80%) patients.122 Similarly, Roy et al. evaluated 28 patients after surgery and 32 after radiation with a suspicion for recurrence and found that sensitivity with T2WI and spectroscopy sequences after surgery was 57% and 53%, respectively, and was 71% and 78%, respectively, after radiation. DCE-MRI alone showed a sensitivity of 100% and 96%, respectively, for post-surgery and post-radiation groups. DWI alone had a higher sensitivity for radiation (96%) than for surgery (71%). The combination of T2WI plus DWI plus DCE-MRI provided a sensitivity as high as 100% for detection of recurrence after radiation.123 Wu et al. conducted a meta-analysis to assess the effectiveness of mpMRI during the follow-up of patients with prostate cancer after undergoing radiation or radical prostatectomy. 14 studies were identified, 7 after surgery and 9 after radiation. DCE images were more sensitive and specific than T2 weighted images, but sensitivity was highest when DCE was combined with spectroscopy for both post-surgical and post-radiation patients.124
- It is possible that mpMRI may be useful for follow up evaluation of men treated with radical prostatectomy or in situ ablative therapies (cryoablation or high frequency focal ultrasound, and radiation therapy). However, current information has not determined the diagnostic accuracy of this imaging modality in these settings.
Use of MRI for Surveillance of Prostate Cancer
The concept of observation as a therapeutic option for men with clinically localized prostate cancer has been well established and is associated with excellent long-term progression-free survival in men with favorable malignancy on prostate biopsy. Chodak et al. demonstrated in a large multi-institutional pooled analysis of 828 men that conservative therapy, also known as watchful waiting, resulted in disease-specific survival of 87% at 10 years for men with either grade 1 (equivalent Gleason sum 5,6) or grade 2 (likely equivalent Gleason sum 7) cancer. The finding that the metastasis-free survival for men with Grade 2 adenocarcinoma was only 58% at 10 years suggested that there was a role for a more active monitoring strategy in some men.125 More contemporary trials, including PIVOT and Protec T, support surveillance rather immediate treatment in contemporary patients, most likely to get diagnosed with serum PSA where the risk of overdiagnosis has been established.126,127
A contemporary modification of the watchful waiting paradigm is considered active surveillance with some percentage of men transitioning from observation to curative intervention following evidence of disease progression most commonly on repeat prostate biopsy. A variety of classification schema have been developed to best identify men with the form of low risk prostate cancer that may be optimally managed with surveillance. The Prostate Cancer Research International Active Surveillance Study (PRIAS) monitored 5,302 men in 18 countries for evidence of disease reclassification over time with a total of 52% and 73% of men moving to intervention at 5 and 10 years.128 Since approximately one-third of men treated with delayed intervention using radical prostatectomy still had favorable pathology (Gleason sum 3+3, pT2) the authors speculated on opportunities to more accurately identify progression so that men could continue on the active surveillance pathway.129
Despite the established outcomes of watchful waiting series, overall survival statistics for comparable active surveillance protocols is still lacking with a wide variety of metrics used to predict the optimal candidates for this approach and to define parameters for transitioning care from surveillance to intervention.130 Conti et al. reviewed 1,097 men treated with radical prostatectomy and discovered that the published criteria for enrollment in active surveillance resulted in a variable risk of disease reclassification on biopsy or with unfavorable pathology at the time of intervention.131 The variability in outcomes relative to the selection criteria applied for enrollment into an active surveillance program was recapitulated by Elamin et al. in 2016.132 Clearly, the optimal implementation of active surveillance for men with low risk prostate cancer is still under development with need for clarity around the type of diagnostic testing and surveillance intensity. However, most would agree that those with low volume, low grade (Gleason grade 3/3 cancer) with PSA densities < 0.15 likely represent initial candidates for such an approach. Intermediate results in several cohorts of patients on active surveillance have been associated with good outcomes.133 However, concerns about misclassification and how best to select and follow such patients are an impediment to more widespread use of active surveillance.134
Several diagnostic modalities are currently being evaluated for enhanced performance in the management of men on active surveillance. A simple change from a transrectal approach for prostate biopsy to transperineal biopsy has been found to more accurately predict clinical risk category but with similar risk of pathologic upgrading.135,136 However, transperineal biopsy has not been widely implemented in practice. Similarly, use of MRI–fusion biopsy techniques may better identify those with high-risk disease. Additional clinical information supports the role of molecular markers; such as genomic profiling, as well as stratification by extent of Gleason score 4 adenocarcinoma in selecting men for active surveillance protocols.137–140 Both PI-RADS scoring and genomic classification have been shown to predict the risk of upgrading in those on active surveillance and although the results of such tests do not necessary exclude men from surveillance shown to have low grade/volume on biopsy, they may identify patients who require more careful and timely follow-up.141 Although the preferred frequency of mpMRI for those on active surveillance has not been determined, most such tests are performed at 12- to 36-month intervals, depending on baseline risk.
Importantly, any information extracted from the prostate biopsy is ultimately limited by the accuracy of the biopsy itself. Recent advances in prostate imaging with ultrasound and mpMRI have been shown to improve the targeting of biopsy to regions in the prostate that are most likely to harbor clinically significant cancer. Therefore, it remains possible that a targeted biopsy under advanced imaging guidance will optimally select men for all therapeutic options including active surveillance. mpMRI has been demonstrated to improve the detection of clinically significant prostate cancer at the time of initial biopsy which could better identify individuals who would not qualify for active surveillance with as many as 10% of men reclassified as higher risk by the MRI targeted biopsy.142,143 A 2015 systematic literature review by Schoots et al. found that mpMRI identifies suspicious lesions, which increases the likelihood of clinically significant disease, in more than 60% of men who would be candidates for active surveillance.144 Therefore, an mpMRI-guided targeted prostate biopsy represents an advance in the determination of clinically significant prostate cancer prior to enrollment in any treatment pathway including active surveillance. Although the current evidence is inadequate to establish that mpMRI-guided biopsy is a required step in the pathway for active surveillance, it is strongly recommended that an mpMRI be performed in men considering active surveillance if they have not already undergone imaging before biopsy.
Once men select active surveillance as a management option for their low risk prostate cancer, the specific details of follow-up represent important costs and treatment intensity concerns. A negative mpMRI, although predictive of non-progression in general compared to those with positive mpMRIs, does not exclude upgrading as 27% of men with negative mpMRIs may experience upgrading. These findings suggest that this imaging modality alone cannot be used to monitor men on active surveillance.144 Use of additional markers of risk such as PSA density and/or genomic profiling complement imaging. An unchanged mpMRI has been associated with an 80% NPV for biopsy upgrading during an active surveillance investigation.145 Guidelines for the use of mpMRI in men on active surveillance have been established.146 It is recommended that those on active surveillance who undergo mpMRI before biopsy undergo both targeted and systematic biopsy techniques because a small but significant number of men may progress outside the target.147
Despite this conclusion, significant opportunities exist for further refinement of active surveillance protocols to better risk-stratify men at initial entry into these protocols and to better target the regions of the prostate that could harbor a malignancy that would require a delayed therapeutic intervention. The combination of advanced imaging with MRI, altered biopsy approaches, (e.g., transperineal), and the use of molecular markers appear to improve the outcomes (e.g., safety, costs) of active surveillance.
- mpMRI has been demonstrated to improve the diagnosis of intermediate-risk and high-risk prostate cancer. Patients with MRIs suggestive of such disease should undergo more careful evaluation, including repeat MRI targeted and systemic biopsies before considering active surveillance. However, the current information about mpMRI is not sufficient to support a role for repeat mpMRI in the absence of any confirmatory prostate biopsy for monitoring men on active surveillance. mpMRI may be used in conjunction with other risk stratification techniques such as PSA density and genomic profiling to enhance the use and safety of active surveillance regimens.
Information obtained by mpMRI represents a significant addition to traditional imaging techniques for the management of prostate cancer. Consensus statements on prostate mpMRI techniques enhances its reproducibly, allowing for standardization of reporting of imaging findings. MRI suspicion score through PI-RADS correlates well with the likelihood of clinically significant cancer, potentially allowing pre-biopsy risk stratification for individualized decision-making. mpMRI in conjunction with ultrasound fusion biopsy detects more clinically significant disease while missing lower volume and clinically indolent disease. Enhanced targeting approaches have the potential to reduce the cost of care through the reduction of unnecessary or inaccurate prostate biopsy procedures along with their attendant risks.
Current evidence now supports the use of mpMRI in men at risk of harboring prostate cancer prior to their first biopsy, as well as in men with a rising PSA following an initial negative standard prostate biopsy procedure. It is likely that mpMRI can be beneficial to men with a presumed clinically localized prostatic cancer prior to selecting definitive therapy. The information obtained from mpMRI appears to offer some useful guidance for surgical planning with both extirpative and ablative treatments.
Enthusiasm for the potential benefit of prostate mpMRI suggests that more evidence will be forthcoming regarding the role of this modality in men managed with active surveillance and possibly in population-based screening programs for prostate cancer. However, current evidence does not support the use of mpMRI as a stand-alone screening test for prostate cancer. These applications should be considered investigational at this time.
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Board of Directors, October 2018 (Reaffirmed), May 2019 (Revised)