L. Michael GlodÃ©, MD, FACP
This article summarizes the current role of multiparametric MRI in the diagnosis, risk assessment, and treatment of prostate cancer.
Prostate cancer remains the only solid tumor diagnosed using transrectal ultrasound–guided sampling of the gland, and not an image-based, lesion-directed approach. This technique has limitations in that it underdiagnoses clinically significant disease and overdiagnoses indolent tumors resulting in overtreatment of patients. Technical advances in MRI in the last decade have made this method the preferred imaging modality for prostate anatomy and for risk assessment of prostate cancer. As of 2018, the indications for MRI in the diagnosis and risk assessment of prostate cancer have expanded from preoperative evaluation to the pre-biopsy setting, as well as for surveillance protocols. This article summarizes the current role of multiparametric MRI in the diagnosis, risk assessment, and treatment of prostate cancer.
Transrectal ultrasound–guided (TRUS) biopsy is considered the standard of care for the diagnosis of prostate cancer in men presenting with elevated prostate-specific antigen (PSA) levels or abnormal digital rectal examination. This systematic sextant extended biopsy approach samples approximately 0.04% of the prostate volume and yields cancer detection rates of only up to 40%. Since TRUS biopsies are not targeted, they can lead to overdiagnosis of clinically indolent tumors, while missing clinically significant prostate cancer foci.
Recently, several advances in prostate imaging have led multiparametric MRI (MP-MRI) to be the preferred imaging modality for detecting areas suspicious for prostate cancer and allowing for targeted biopsy sampling. Once these areas have been identified, targeted biopsies can be performed using three methods: in-bore MR-guided biopsy, cognitive fusion biopsy, and software-based fusion biopsy. In-bore biopsy involves performing the biopsy with the patient in the MR gantry; cognitive fusion involves using the MRI to estimate the location of the lesion during the ultrasound procedure; and software-based fusion platforms (UroNav, Artemis, Koelis, etc) use complex algorithms to register and simultaneously display MR and TRUS images to guide targeted biopsies.[2,3] Research on MP-MRI and targeted biopsies is ongoing, providing radiologists and urologists with more evidence on their use in the detection and risk stratification of prostate cancer. Herein, we present a summary and our perspective on how to apply this literature to clinical practice.
Overdiagnosis and overtreatment of indolent prostate cancer is a major concern. As a result, the focus has shifted from merely detecting prostate cancer to identifying clinically significant disease. MRI can identify suspicious areas for cancer and allows for targeted biopsies of these regions.
In a study by Siddiqui et al, 1,003 patients underwent MRI plus concurrent targeted and systematic biopsy sampling. Targeted biopsy detected 30% more high-risk cancers and 17% fewer low-risk cancers compared with the systematic approach. A limitation of this study was its retrospective nature and heterogeneous population. In an attempt to answer this question in prospective randomized trials including only biopsy-naive patients, recent data from the PROMIS study showed that in patients with elevated PSA levels and no prior biopsy, MRI could help safely avoid 25% of unnecessary biopsies. In this study, all patients with elevated PSA levels underwent a 1.5 Tesla MRI. If they had a suspicious lesion on imaging, they underwent transperineal mapping biopsy (as control) plus standard systematic 12-core biopsy. The primary definition used for clinically significant cancer was a Gleason score ≥ 4+3 or median core length (MCL) ≥ 6 mm for which MRI demonstrated a negative predictive value of 89% and a sensitivity of 93%, which is concordant with other previous results published in the literature.
Recently, data from the PRECISION study was published to answer the question of whether MRI plus targeted biopsy yields superior results compared with the standard approach. Five-hundred patients with elevated PSA levels and no prior biopsy were randomized to MRI/targeted biopsy vs standard biopsy. If the MRI showed a lesion with a Prostate Imaging Reporting and Data System (PI-RADS) score ≥ 3, the patient underwent targeted biopsy only. The primary outcome was detection of clinically significant prostate cancer defined as Gleason score ≥ 3+4. Clinically significant cancer was detected in 38% of men in the MRI/targeted biopsy group vs 26% in the standard biopsy group (P = .005). Furthermore, the MRI/targeted biopsy group detected fewer clinically insignificant cancers compared with standard biopsy (9% vs 22%; P = .05). The authors stated that MRI with or without targeted biopsy was noninferior to the standard approach. Considering the newest data, increasing evidence supports a possible role of upfront MRI in the biopsy-naive setting. However, since most urologic guidelines do not recommend this approach, it is still not widely adopted as the standard of care.
A particular challenge exists when a patient presents with a persistently elevated PSA level and a negative systematic biopsy. Several approaches, including repeat sextant extended biopsies, anteriorly directed core biopsies, and saturation and transperineal template biopsies, have been attempted to rule out prostate cancer.[7,8] However, since none is targeted to any area of known suspicion, they have yielded inconsistent results. Vourganti et al reported that for 195 men with elevated PSA levels and prior negative biopsies, MRI/ultrasound fusion biopsy plus 12-core TRUS biopsy detected prostate cancer in 37% of patients, 11% of whom had a Gleason score ≥ 8. Standard TRUS biopsy missed 55% of high-grade tumors. Similarly, in a series of 105 patients, Sonn et al reported that targeted biopsy detected more clinically significant prostate cancers and less clinically insignificant cancers compared with TRUS biopsy alone.
Detection of clinically significant cancer in a re-biopsy setting is up to 54%. Sufficient evidence supports a targeted approach in the setting of elevated PSA levels following a negative TRUS biopsy. However, little evidence compares targeted approaches. The National Comprehensive Cancer Network and the American Urological Association recommend MRI and targeted biopsy after one prior negative biopsy.[11-13] The Figure shows a proposed flow diagram for the use of MP-MRI.
Various management options are available for low-risk prostate cancer, from active surveillance to radical treatments, including radical prostatectomy and radiation therapy. Low-risk prostate cancer can harbor either indolent disease or slowly progressive cancer, so safe monitoring for a period of time is possible without losing the window of opportunity to treat the cancer with curative intent when it progresses to higher-risk disease. However, for active surveillance protocols to be effective, they require accurate risk assessment, which means adequate characterization of tumor grade and volume at diagnosis, as well as assertive evaluation of disease progression.
The problem with current active surveillance protocols is that adequate characterization of tumor grade/volume at diagnosis and evaluation of disease progression cannot be reliably assessed with direct comparison to prior sampling using a systematic biopsy approach. Studies have shown that up to 30% of active surveillance candidates are upstaged to higher-risk disease on confirmatory biopsy. This could be partly explained by the random nature of standard prostate biopsies, which tend to underestimate the burden of disease. Consequently, active surveillance candidates may harbor occult high-risk prostate cancer in lesions missed by a standard biopsy approach. MRI offers the advantage of high image quality for clinical use in this population, providing a high negative predictive value.
L. Michael GlodÃ©, MD, FACP
The rapidly evolving use of multiparametric MRI in directing prostate biopsies is an exciting advance in the care of prostate cancer patients. Evidence is accumulating, as reviewed in this timely article, for incorporating the technology both in the initial evaluation of patients prior to their first biopsy, as well as in the setting of active surveillance or in those cases where a high degree of clinical suspicion exists and the initial biopsy has been negative. As the authors correctly point out, there should be ongoing feedback between the urologist, pathologist, and radiologist to optimize the accuracy and utility of multiparametric MRI implementation. In addition, clinicians will need to learn how to integrate the expanding list of molecular markers for risk of high-grade disease into the algorithm of care. Finally, we must continue to evaluate the cost-benefit ratio of these newer technologies, which is complex, given the dire implications (and eventual costs) of missing high-grade early prostate cancer.
Dr. GlodÃ© is Professor, Division of Medical Oncology/Robert Rifkin Chair for Prostate Cancer Research at the University of Colorado Denver
Several studies have found MRI can rule out clinically significant cancer, with negative predictive values ranging from 67% to 100%.[14–16] This allows us to counsel patients diagnosed with low-grade and low-volume disease and no visible lesions on MRI who are seeking active surveillance on the low likelihood of presenting with clinically significant prostate cancer. MRI is also useful in risk stratification and diagnosing clinically significant cancer, determined primarily by International Society for Urological Pathology grade on biopsy specimen, which is crucial in counseling patients on best treatment options.
In a study by Stamatakis et al, 85 patients who were active surveillance candidates according to Epstein criteria underwent confirmatory MRI/ultrasound fusion targeted biopsy and systematic biopsy, after which 29% (25 patients) no longer met the active surveillance protocol criteria. Similarly, in a study by Hu et al, confirmatory fusion biopsy for men on active surveillance resulted in reclassification of 36% of patients. Men presenting with higher-grade lesions on MRI (grades 4 and 5) were 3 times more likely to be reclassified (odds ratio, 3.2; 95% CI, 1.4–7.1; P = .006).
In a recent study published by Recabal et al, 206 patients with Gleason 3+3=6 disease who were active surveillance candidates underwent MP-MRI and targeted biopsy. The researchers reported that 66% of patients presented with regions of interest on their MRI, and 37% were subsequently reclassified upon biopsy. The efficacy of MP-MRI with targeted biopsy has been confirmed by other studies that have shown that two-thirds of patients on active surveillance harbor suspicious lesions on MRI, and this increases their likelihood of presenting with clinically significant prostate cancer on repeat biopsy.[20,21] It has been established that MRI improves the diagnostic yield of intermediate- and high-risk prostate cancer by using a targeted approach. This has been of use in identifying safe candidates for active surveillance protocols, and the use of MRI has been shown to increase the confidence and use of active surveillance. However, it must be noted that current data support its use as an adjunct to a standard diagnostic approach.
Despite prostate MRI being used worldwide, achieving accurate, consistent interpretations continues to be a challenge. PI-RADS has been of great value in unifying criteria and standardizing terminology.
However, it is still a work in progress. There is limited literature evaluating the learning curve of radiologists and how to best implement this technology in the clinic. Despite this, there is consensus that there should be a multidisciplinary effort between urologists, radiologists, and pathologists to enhance image interpretation and utilization in order to achieve the most accurate biopsy results. It appears that the best outcomes are achieved when the radiologist is exposed to a high volume of cases, but also has access to both direct feedback from more experienced colleagues and the patient’s pathology results, as well as through direct participation in focused educational initiatives, such as multidisciplinary tumor boards to enhance the interpretation of prostate MRI images.
MP-MRI is the preferred imaging modality for prostate anatomy and for risk assessment of prostate cancer. It has proven to be useful in the setting of prior negative biopsies, diagnosis of clinically significant disease, and risk characterization of possible active surveillance candidates. Growing evidence supports its superior detection of clinically significant disease in biopsy-naive patients with elevated PSA levels. However, care must be taken since the implementation of the MRI/targeted biopsy approach requires a multidisciplinary effort, in order to provide appropriate quality and interpretation of images, as well as an effective biopsy to ensure optimal results. One major issue that remains is its high cost, which may improve once the technology becomes more available and more physicians become proficient in the associated biopsy techniques.
Financial Disclosure:Dr. Rais-Bahrami is a consultant for Philips/Invivo Corporation. Dr. Walton-Diaz has no significant financial interest in or other relationship with the manufacturers or providers mentioned in this article.
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