Curr Urol Rep (2014) 15:390 DOI 10.1007/s11934-013-0390-1


Multiparametric Magnetic Resonance Imaging in the Management and Diagnosis of Prostate Cancer: Current Applications and Strategies Daniel J. Lee & Hashim U. Ahmed & Caroline M. Moore & Mark Emberton & Behfar Ehdaie

# Springer Science+Business Media New York 2014

Abstract Magnetic resonance imaging (MRI) has become increasingly used worldwide in the diagnosis and management of prostate cancer. With advances in multiparametric MRI (mpMRI) technology, such as the use of dynamic contrast-enhanced and diffusion-weighted imaging sequences, observational studies have evaluated the utility for mpMRI in the continuum of prostate cancer management, from improving the detection of clinically significant prostate cancer, to planning radical prostatectomy and radiation therapy and the early detection of local recurrence. Furthermore, the potential for advanced imaging to reduce the burden of routine serial prostate needle biopsies for men on active surveillance is a promising area of research. MRI technology continues to evolve, and the potential applications in the management of prostate cancer care will require welldesigned multi-institutional prospective clinical trials and

This article is part of the Topical Collection on Prostate Cancer D. J. Lee Department of Urology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, NY, USA H. U. Ahmed : C. M. Moore : M. Emberton Department of Urology, University College London Hospitals NHS Foundation Trust, London, UK H. U. Ahmed : C. M. Moore : M. Emberton Division of Surgery and Interventional Sciences, University College London, London, UK B. Ehdaie (*) Department of Surgery, Division of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA e-mail: [email protected] B. Ehdaie Department of Biostatistics and Epidemiology, Health Outcomes Group, Memorial-Sloan Kettering Cancer Center, New York, NY, USA

rigorous efforts to standardize reporting and improve dissemination of expertise across institutions. Keywords Prostate cancer . Multiparametric magnetic resonance imaging . Active surveillance . Prostate-specific antigen (PSA) . Management . Diagnosis

Introduction Prostate cancer (PCa) is a common but clinically heterogeneous disease, with more than 900,000 cases diagnosed globally each year [1]. Many of these men will have aggressive disease, with up to 40 % of men experiencing disease progression after primary treatment [2]. Many others, however, will have indolent disease that will not threaten their health during their natural lifespan [3], and they may experience morbidity and compromised quality of life from prostate cancer treatment [4••]. Despite two large cancer-screening trials with conflicting data regarding the benefits of prostate cancer screening [5, 6] the recent review by the U.S. Preventive Services Task Force [7] found that the use of prostatespecific antigen (PSA) in screening for PCa was associated with significant harm and could severely impact the quality of life due to the risks associated with treatment for localized PCa. Pretreatment predictive models using nomograms from several large studies [8–10] have helped improve risk stratification and the personalization of treatment strategies according to clinical and pathologic characteristics. Active surveillance (AS) is a disease management strategy that may delay or avoid curative treatment for low-risk disease in select men. One commonly used stratification is the “Epstein criteria,” with low risk consisting of a Gleason of 6 on biopsy, no more than two positive cores, no involvement of more than 50 % of a core, and PSA2 cm, between 1–2 cm, and 0.5–1 cm, the detection rates were approximately 89 %, 45 %, and 13 %, respectively, with an overall tumor detection accuracy of 93 % [35]. Dynamic Sequencing in MRI The use of functional parameters such as DCE and DWI in addition to anatomical T2-weighted sequences has improved the diagnostic applicability of MRI. DCE involves the rapid acquisition of images after administering intravenous paramagnetic contrast, where contrast is taken up and released more quickly in PCa cells. DWI uses the differential movement of water in the interstitial space to reflect architectural features of the tissue. PCa has higher cell densities and abundant cell membranes, and therefore shows restricted diffusion patters, with a high signal on longer b-value sequences and a low signal on the apparent diffusion coefficient (ADC) map. The use of mpMRI has significantly improved the sensitivity and specificity of PCa detection. Jager et al. [36] found improvement in sensitivity from 57 % to 73 % when DCE was used, while Haider et al. [37] reported an increase in sensitivity from 54 % to 81 % when DWI was added to standard T2weighted MRI. Importantly, the improvement in sensitivity was noted in the detection of clinically significant PCa, which was defined as a Gleason score >6 and tumor diameter >4 mm [37]. One of the potential confounders in comparing mpMRI accuracy to the radical prostatectomy specimen is the possible deformation of specimens during processing and the resulting mismatch between histopathology and imaging findings. In a study that controlled for this potential confounder by securing a mold to match each MRI image with the corresponding prostatectomy pathology slice, mpMRI was found to have a positive predictive value of 98 %, with significantly improved

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sensitivity in patients with Gleason grades 4 or 5 [38]. In addition, ADC values can help differentiate aggressive from low-grade PCa, in which restricted diffusion correlates with higher Gleason grade [39]. Multiparametric MRI and Tumor Aggressiveness Multiparametric MRI has also been useful in assessing tumor aggressiveness. Low-grade tumors have been found to have low tumor cellularity mixed with various amounts of normal prostatic stroma, while higher-grade tumors have higher cellularity density and loss of glandular duct formation, which indicates that the space for free water movement reduces as the Gleason grade increases [40]. Several studies have demonstrated that mpMRI can improve the prediction of highgrade disease in biopsy and pathologic specimens with high diagnostic accuracy [41–44]. In an analysis of patients who had Gleason 3+3 disease on biopsy and proceeded to have a radical prostatectomy, ADC values were significantly lower in those samples that were then upgraded compared to those that remained Gleason 3+3 on pathology review [45]. The use of mpMRI has also helped to improve the prediction of extracapsular extension and seminal vesicle invasion by identifying anatomical changes such as the degree of capsular abutment, bulge, and irregularity [46]. Role of MRI in Treatment Planning The ability to localize and map tumor foci is especially helpful in preoperative planning for radical prostatectomy. In a study of 75 patients that underwent radical prostatectomy for PCa, Labanaris et al. [47] analyzed the risk of extracapsular extension to determine the relative safety of neurovascular bundle preservation. Based on the mpMRI findings, the operative strategy was changed 44 % of the time; ultimately, the accuracy of mpMRI in predicting seminal vesicle invasion, extracapsular extension, and neurovascular bundle was 92 %, 100 %, and 100 %, respectively. These results indicate that the use of mpMRI can influence surgical management and optimize preservation of neurovascular bundles. Future studies will need to report outcomes of incorporating mpMRI information for surgical planning and include surgical margin data and disease-specific recurrence. The success of radiotherapy in PCa treatment depends on adequate treatment coverage, and consequently depends on imaging modalities that are able to clearly define the tumor boundaries. MRI demonstrates significantly better visualization and delineation of the extent of PCa compared to CT, especially at the prostatic apex [48]. This allows for improved delineation of the irradiation field to maximize the localization of treatment to the tumor and minimize the dose to periprostatic tissue and the urethra.

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The Role of MRI in Active Surveillance Active surveillance (AS) is a management option for low-risk PCa focusing on the identification of low-risk PCa that would have a low likelihood of future progression, in order to mitigate the overtreatment of indolent disease and potentially harmful side effects of treatment. Although current AS cohorts have reported low PCa mortality rates utilizing their selection criteria for entry into AS and triggers for treatment [12••, 49–52], the current prostate biopsy results in pathologic understaging in 30 % of cases [13, 14]. With the advances in mpMRI and its ability to improve the prediction of low- and high-risk disease, mpMRI may be used to help select for entry into AS and to monitor patients on AS. In a study of 388 men with low-risk disease who underwent endorectal MRI prior to a confirmatory biopsy, Vargas et al. [53•] found that low suspicion for a prostatic lesion on MRI had a negative predictive value of 96 % and specificity of 95 % for low-risk disease, while suspicious lesions on MRI was highly sensitive for upgrading on the confirmatory biopsy (87 %–98 %). Future studies should seek to define mpMRI characteristics longitudinally to trigger reclassification biopsies. Accuracy of MRI in Predicting PCa Several nomograms have been constructed to predict the probability of pathologically significant PCa [54–57]. In several retrospective studies, the incorporation of mpMRI characteristics in established predictive models significantly improved their predictive accuracy [58–61]. Shukla-Dave et al. [62•] demonstrated that magnetic resonance models performed significantly better than base clinical model (P≤0.05 for all) and similarly to the more comprehensive clinical models when MRI data was included with known clinical and pathologic factors to predict insignificant disease. The improvement in accuracy using MRI data remained even if the length of cancer in the biopsy core was excluded, an important factor in an established preoperative nomogram [62•]. Among a cohort of patients eligible for AS who underwent mpMRI and subsequent MRI-ultrasound registration-guided biopsies, Stamatakis et al. [63] found that the number of MRI-identified lesions, highest degree of suspicion for cancer on MRI, and lesion density were the most significant predictors of failing eligibility for AS on repeat biopsy. A predictive model was constructed using these factors, with a negative predictive value reported of 80-90 % for confirming eligibility for AS. These findings indicate that mpMRI may be useful in the selection of low-risk PCa for entry into AS, and that it may help to reduce the number of confirmatory biopsies performed based on mpMRI criteria. The use of mpMRI may help mitigate morbidities and costs associated with repeat prostate biopsies. An ongoing

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prospective study, the Prostate MRI Imaging Study (PROMIS), will help to further substantiate the role of mpMRI in predicting clinically significant cancer compared to a standard TRUS biopsy, and will provide information on the costeffectiveness of mpMRI. The utility of mpMRI for men with PCa followed on AS is understudied. In a longitudinal study of 50 patients on AS who underwent serial mpMRI, Morgan et al. [64] reported a significant decrease in ADC values in the tumor and the whole prostate of patients with disease progression that required treatment compared to those who did not progress. In an abstract presented at the European Association for Urology, Stevens et al. [65] reported on 91 men on AS who had repeated mpMRI, and found that 98.6 % of the men (70/71 men) who did not have evidence of radiological progression, defined as an increase in size or intensity, did not have disease progression and remained on AS. Large prospective trials will help to establish and validate the role of serial mpMRI for men on AS. Furthermore, recent studies have incorporated mpMRI data as a determinant of disease outcome. One important prospective trial, MRI in Primary Prostate cancer after Exposure to Dutasteride (MAPPED) [66], that compares dutasteride to placebo for men on active surveillance is the first prospective trial using criteria on mpMRI as a primary endpoint, and could provide useful models for future trials.

Application of MRI to Prostate Biopsy Techniques An active area of research is in the utilization of mpMRI to help target biopsies toward areas of anatomical and functional suspicion. Currently, three MRI-guided prostate biopsy techniques exist: visual registration, which involves a visual transfer of the spatial information of a lesion within the prostate from the MRI images or pictorial report to the ultrasound image used to perform the biopsy; direct MRI-guided biopsy, where biopsies are performed in the MRI machine; and the MRI/ultrasound (MRI/US)-fusion-guided biopsy, where the mpMRI is fused with real-time ultrasound [67]. A systematic review of over 50 trials comparing MRIguided biopsy techniques to standard systematic biopsy in patients without a prior biopsy reported suspicious findings on MRI in 62 % of men [67]. Sixty-six percent of the men with suspicious findings on MRI had PCa on biopsy [67–69], compared to an overall detection rate of 50 % by the standard systematic biopsy technique. In a pooled analysis of all biopsies per core in cohorts who underwent either an MRI-targeted or standard systematic biopsy, cancer was detected in 30 % of MRI-targeted cores, compared to 7 % of standard systematic biopsy cores, demonstrating an advantage for the MRItargeted technique. In a large prospective trial of approximately 1,400 biopsy-naïve patients, Watanabe et al. [70••] found that high ADC values were correlated with significantly

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higher PCa detection rates (70 % vs. 48 % for lower ADC values, p5 mm or any Gleason pattern >3, Haffner et al. [68] found that clinically significant prostate tumors were misclassified in 2 % of cases using either the MRI-targeted biopsy or standard systematic technique, whereas insignificant PCa was detected in 10 % of men with the standard systematic technique compared to no cases using the MRI-targeted approach. This study also noted that the targeted biopsies showed a 16 % greater detection of Gleason grades 4 and 5 PCa compared to the standard systematic technique [68]. In cases with no suspicious lesions identified on MRI, 23 % harbored cancer on standard systematic biopsy [67–69]. However, only 2.3 % of these patients had clinically significant cancer that would have been misclassified by MRI-targeted biopsy alone. In a prospective study comparing 3 T mpMRI-guided biopsies with standard systematic biopsies and their concordance to the final pathology on radical prostatectomy specimens [72], the concordance rate of MRI-targeted biopsies was significantly higher than standard systematic biopsies for detecting Gleason grades 4 and 5 tumors (91 % vs. 46 %, p=0.01 for Gleason 4; 73 % vs. 30 %, p=0.02 for Gleason 5). In a prospective trial of 582 patients who underwent a standard systematic 12-core TRUS biopsy and an MRIguided biopsy of suspicious lesions in the same patient [73••], the addition of the MRI-targeted biopsy supported Gleason grade upgrading in 32 % of the cases and was able to detect 67 % more Gleason 4 and 5 tumors than the standard systematic biopsy alone. On a multivariable analysis, suspicion of PCa on mpMRI was independently associated with Gleason score upgrading (OR 1.7, p=0.04). In a validation cohort observational study in men with elevated PSA without prior biopsy, the diagnostic performance of mpMRI to detect PCa was evaluated using transperineal template prostate mapping biopsy. The negative and positive predictive values to detect PCa based on different definitions of significant disease were 84 %–89 % and 49 %–63 %, respectively [74]. Despite a consistently reported improved accuracy compared to TRUS

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biopsy across studies, the performance characteristics of mpMRI varied considerably based on definitions of significant disease, prevalence of disease in cohorts studied, and the number of segmented sectors of the prostate used in the analysis. MRI-Targeted Biopsies in Patients with Prior Negative Biopsies MRI-targeted biopsies can have a particularly useful application in patients with prior negative biopsies but continued clinical suspicion of PCa. In a pooled analysis of men with at least one negative prior biopsy, 69 % had a suspicious lesion on MRI, with 70 % of those lesions positive for PCa [67, 75–77]. In patients with persistently high PSA levels but prior negative biopsies, two prospective trials found that the addition of mpMRI to PCA3 in predictive models showed significant improvement in the prediction of PCa compared to a base model, with an AUC>0.80 in both studies [78, 79]. Therefore, mpMRI can provide clinically significant information, independent of standard clinical characteristics, in men with prior negative biopsies but persistently elevated PSA, and could reduce unnecessary repeat biopsies. MRI Imaging After Prostate Biopsy Changes on T2-weighted and DCE sequences in MRI can persist for at least 8 weeks after a prostate biopsy [80, 81] and can significantly decrease staging and detection performance. In a study that compared mpMRI accuracy for detecting PCa when performed less than or more than 3 weeks after a prostate biopsy, the accuracy decreased from 83 % to 46 % if performed within 21 days of biopsy [82]. In a recent consensus report [46], staging MRI was recommended at least 10 weeks after a biopsy, but preferably after 20 weeks. The consensus also recommended that the mpMRI scan be done prior to the biopsy when possible.

MRI Imaging After Primary Treatment Recurrence after definitive treatment for PCa, including radical prostatectomy and radiation therapy, is usually defined by an increase in the serum value of PSA after reaching the nadir. The RTOG-ASTRO Phoenix consensus assessed that a rise by 2 ng/ml or more above nadir is the standard definition of biochemical failure (BCF) after radiation therapy, while BCF after radical prostatectomy is defined as a PSA>0.2 ng/ml in two subsequent levels [83, 84]. PCa recurrences are usually classified into PSA-only relapse, local recurrence, distant metastasis, or a combination of local and distant metastasis.

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MRI has been used to evaluate the prostatic fossa after prostatectomy, and allows for an evaluation of the pelvis, pelvic lymph nodes, and bone status. In general, local recurrences were noted to be hyperintense signals on T2weighted sequences [85], but these can be confused with the signal intensity often seen with post-treatment fibrosis. The use of DCE sequences can significantly improve the accuracy of detecting local recurrence; several studies have shown that the use of DCE can improve the sensitivity and specificity to above 80 %, compared to accuracy of approximately 40–60 % with standard T2-weighted MRI [86, 87]. Similarly, diagnosing local recurrence after radiotherapy is especially challenging because of the radiationinduced fibrosis, leading to low sensitivity and specificity to detect recurrence for TRUS [88]. The use of T2weighted imaging alone does poorly in predicting local recurrence. The addition of DCE sequences, however, significantly increases the accuracy of MRI after radiation therapy [89], with sensitivities ranging around 72 % and specificities up to 85 % [90]. In a study comparing recurrence detection rates by MRI and TRUS among 172 patients undergoing external beam radiotherapy, Kara et al. [91] found that the sensitivity and specificity in predicting recurrence on TRUS were 53.3 % and 60 %, respectively, compared to 93 % and 100 %, respectively, for MRI [92].

MRI in Focal Therapy Focal therapies, including brachytherapy, cryotherapy, and HIFU, have been used in the salvage setting in radiorecurrent PCa, but are increasingly used as an alternative primary treatment strategy in select patients. The general efficacy and safety of these treatments are dependent upon accurate localization of tumors prior to and during treatment [93]. In addition, it is important to detect possible morphologic changes within the tumor to assess treatment response. The use of MRI to select patients for focal ablative therapy is especially appealing, as MRI could be utilized to localize PCa and to determine if it is unifocal or confined to one lobe of the prostate. Although unifocal lesions represent only a small proportion of PCa [94], the use of MRI would help distinguish index lesions defined by Gleason grade or volume, and then would enable real-time guidance during treatment. Currently, the efficacy of mpMRI to detect recurrence after focal tumor ablation is understudied. MRI-guided therapy has advantages over TRUS-guided therapy because of its ability to localize and characterize tumors and to monitor therapy using MR thermography [95]. MRI-guided placement of brachytherapy seeds has been very successful in providing accurate treatment coverage for PCa [96, 97], and animal models have demonstrated similar

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results with MRI-guided focal HIFU [98]. Focal laser ablation has been described using MRI-guidance with the use of MR thermometry to monitor efficacy of treatment in real time [99]. As focal ablative therapies advance, prospective studies are necessary to validate the performance of mpMRI in predicting treatment response and detecting disease recurrence during follow-up. In patients undergoing ablative therapies such as HIFU, cryotherapy, and photodynamic therapy, mpMRI has been used to assess treatment effect. A mpMRI within one week after focal HIFU therapy demonstrating nonenhancement within the prostatic parenchyma demarcated by a peripheral rim of enhancing prostatic parenchyma [100] is reported to correlate histologically with the zone of necrosis and effective treatment area [101]. Six months after ablative therapy, the area of necrosis has usually been replaced by fibrosis and appears as a decreased T2 signal intensity [100]. In a study of 10 patients undergoing HIFU, those who had a PSA

Multiparametric magnetic resonance imaging in the management and diagnosis of prostate cancer: current applications and strategies.

Magnetic resonance imaging (MRI) has become increasingly used worldwide in the diagnosis and management of prostate cancer. With advances in multipara...
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