The Emerging Role of MRI in Prostate Cancer Active Surveillance and Ongoing Challenges

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1 Genitourinary Imaging Review Barrett and Haider Role of MRI in AS of Prostate Cancer Genitourinary Imaging Review Tristan Barrett 1 Masoom A. Haider 2 Barrett T, Haider MA Keywords: active surveillance, multiparametric MRI, prostate cancer DOI: /AJR Received February 17, 2016; accepted after revision July 6, T. Barrett is supported by the Cancer Research UK and Engineering and Physical Sciences Research Council Imaging Centre in Cambridge and Manchester and the NIHR Biomedical Research Centre. 1 Department of Radiology, Addenbrooke s Hospital and the University of Cambridge, Hills Rd, Cambridge, CB2 0QQ, UK. Address correspondence to T. Barrett (tb507@medschl.cam.ac.uk). 2 Department of Medical Imaging, Sunnybrook Health Sciences Center and University of Toronto, Toronto, ON, Canada. AJR 2017; 208: X/17/ American Roentgen Ray Society The Emerging Role of MRI in Prostate Cancer Active Surveillance and Ongoing Challenges OBJECTIVE. Active surveillance (AS) has emerged as a management strategy for preventing overtreatment of indolent prostate cancer. Selection of patients for AS has traditionally proved challenging and resulted in 20 30% misclassification rates. MRI has potential to help overcome this limitation, broaden selection criteria to increase recruitment, and minimize the invasive nature of AS follow-up. CONCLUSION. The main issues surrounding MRI and AS are the heterogeneity of inclusion criteria, the definition of significant disease, and agreement about what constitutes radiologic progression. Prospective cohorts with MRI at enrollment and long-term follow-up are required to further address these issues. P rostate cancer is the second leading cause of cancer death in men worldwide, and its incidence is expected to double by 2030 in part because of the aging global population [1]. Although there is debate about whether the introduction of prostate-specific antigen (PSA) screening is responsible for the steady reduction in prostate cancer related deaths [2], there is little doubt about its effect on the rate of prostate cancer diagnosis [3]. PSA screen detected cancers have a substantially higher likelihood of being indolent, and these tumors show both lower grade and lower volume at presentation [4]. This has resulted in the overdiagnosis of clinically insignificant cancer that would not otherwise have resulted in symptoms or cancer-related death [5]. The risk of overdiagnosis is resultant overtreatment. It is estimated that in screen-detected populations, 48 men will need to undergo treatment to prevent one death from prostate cancer [6]; this ratio (48:1) compares unfavorably with that for breast cancer screening programs (3:1) [7]. Overtreatment of prostate cancer often results in significant side effects. Approximately 60% of patients will experience erectile dysfunction after radical therapy, and although the rates of severe urinary incontinence are low, as many as 30% of patients continue to report some symptoms at long-term follow-up [8, 9]. Active surveillance (AS) has therefore emerged to address this problem and is now recommended as the management strategy of choice in men with low-risk localized prostate cancer for whom radical therapy is suitable [10, 11]. One of the barriers to widespread acceptance of AS for men with prostate cancer is the risk of underestimating the extent of cancer and missing the opportunity for cure (Appendix 1). Typically, AS enrollment is based on histology results from a transrectal ultrasound (TRUS)-guided biopsy; however, TRUS-guided biopsy randomly samples 1% of the gland and is therefore prone to sampling error [12]. It is well established that TRUS biopsy underestimates prostate cancer aggressiveness in approximately one-third of cases [13], underestimates volume in one-half of cases, and may miss 30 40% of clinically significant tumors [14]. As a result, patients with disease that appears to progress within the first 1 2 years of diagnosis are more likely to represent cases of initial misclassification of a more aggressive cancer rather than dedifferentiation of an indolent tumor [15 17]. Multiparametric MRI incorporating anatomic and functional sequences has now been extensively validated for the detection of prostate cancer, and evidence suggests baseline MRI can help to identify these misclassified patients and immediately exclude them from AS [18]. MR images offer additional information on locoregional staging, and whole-gland imaging is of particular AJR:208, January

2 Barrett and Haider A B C Fig. 1 Value of MRI at enrollment for active surveillance (AS). In this example, patient is 77-year-old man with prostate-specific antigen value of 7.7 ng/ml. Transrectal ultrasound guided biopsy showed Gleason disease in three of six left-sided cores with positive findings in less than 5% of each core. Initial treatment plan was AS with transurethral resection of prostate for outflow symptoms. A, Axial T2-weighted image shows large left-sided anterior transition zone (TZ) lesion (asterisk) crossing midline with extraprostatic extension. B and C, TZ lesion appears markedly hyperintense on DW image (B) and hypointense on apparent diffusion coefficient map (C). Subsequent targeted biopsy confirmed Gleason disease in 80 90% of cores. Patient subsequently received combined androgen deprivation and radiotherapy. benefit in identifying anterior disease (Fig. 1), which is not only impalpable on rectal examination but also systematically missed by standard TRUS-guided biopsy [19] (Appendix 2). In this article, we summarize the evolving role of MRI in AS protocols and the ongoing challenges that need to be addressed. Selection of Patients for Active Surveillance Although AS had been widely used on an ad hoc basis, it was only in the early 2000s that the concept of AS as a management strategy emerged and the distinction was made between AS and watchful waiting with a palliative intent [20]. The first reports on expectant management soon followed [21] with the Prostate Cancer Research International Active Surveillance (PRIAS) study [22] emerging in 2007 from the European TABLE 1: Differences in Active Surveillance Enrollment Criteria a Institution [Reference No.] Gleason Grade PSA (ng/ml) Randomized Study of Screening for Prostate Cancer (ERSPC). Although there is now a growing consensus that patients with low-risk indolent disease should be offered AS as a management option, there is a lack of agreement about what constitutes significant disease. A clinical definition of significant disease would be disease that poses significant health risks; however, in practice, biochemical and pathologic surrogates are used. Features of locally advanced disease such as extraprostatic extension, seminal vesicle invasion, or nodal or bone metastases are clearly associated with higher-risk disease. For organ-confined disease, differentiation of low-risk disease from intermediate- to high-risk disease typically relies on PSA markers, biopsy-derived Gleason grade, and implied tumor size. The Gleason system incorporates two grades of tumor pattern and can be reported either as the Gleason grades of individual components, the first grade being the more prevalent tumor pattern (e.g., Gleason grade 3 + 4), or as a summed score (e.g., Gleason score 7). The Gleason score is the key factor that trumps either tumor volume or PSA levels. Although a Gleason score 6 without a Gleason grade 4 or 5 is a commonly used criterion for low-risk cancer [23], some centers enroll patients with prominent but not predominant grade 4 disease (i.e., Gleason 3 + 4) tumors to AS [22]. The heterogeneity of the inclusion criteria used by different centers makes comparisons of studies more challenging (Table 1). For the purposes of patient enrollment in AS, tumor volume is derived from the number of biopsy cores from a standard TRUS-guided acquisition that are positive (typical AS enrollment criteri- PSAD (ng/ml/ml) Stage Cores Positive European Randomized Study of Screening for Prostate T2 2 cores Cancer sites [22] Johns Hopkins Hospital [26] T1 2 cores or 50% of a core Memorial-Sloan Kettering Cancer Center [87] T2 3 cores or 50% of a core Royal Marsden [88] T2a 50% of a core University of Toronto [89] or 15 b T2b or b University of California, San Francisco [56] T2 33% cores of all cores or 50% of a core University of Miami [90] T2 2 cores of all cores or 20% of a core Note PSA = prostate-specific antigen, PSAD = prostate-specific antigen density. a Adapted with permission from [56]: Cooperberg MR, et al.: J Clin Oncol Vol. 29 (issue 27), 2011: American Society of Clinical Oncology. All rights reserved. b Patients 70 years old for the first 5 years of the program. 132 AJR:208, January 2017

3 on 2 cores positive) or from the percentage of core involvement (typical AS enrollment criterion 50% of a core) [22, 24 26]. MRI has the potential to more accurately define tumor volume and has shown improved performance over clinically based models for identifying patients suitable for AS programs [27]. Based on a series of patients undergoing cystoprostatectomy for bladder cancer, Stamey et al. [28] proposed that a tumor volume of > 0.5 cm 3 represents significant disease irrespective of tumor grade. However, more recent work by Wolters et al. [29] based on a screened population suggests that tumors in patients with lowergrade (Gleason score 6) disease should be considered insignificant up to a volume of 1.3 cm 3. A C Role of MRI in AS of Prostate Cancer MRI for Enrollment of Patients in Active Surveillance Programs Prostatectomy data in patients otherwise meeting AS enrollment criteria suggest that the initial biopsy misclassification rate is on the order of 20 30% [30, 31]. These results are supported by early rebiopsy results that lead to upgrading of 27% of cases to a Gleason score of 7 and, interestingly, to negative findings in a similar proportion of patients [32]. Current clinical guidance in the United Kingdom now recommends multiparametric MRI before enrollment in AS programs with the aim of identifying and excluding these patients [10]. A recent meta-analysis showed that MRI identifies a suspicious lesion in two-thirds of men otherwise suitable for AS [33]. However, Fig. 2 Disease progression on active surveillance. In this example, increase in lesion size was detected on follow-up MRI of 62-year-old man with initial prostate-specific antigen (PSA) value of 6.61 ng/ml. A, Baseline MR image shows mm lesion (arrow) at right anterior apex. B, Baseline apparent diffusion coefficient (ADC) map shows low-signal-intensity lesion (arrow) with restricted diffusion and ADC value of mm 2 /s that corresponds to lesion seen in A. Targeted biopsy of right anterior apex transition zone at baseline showed Gleason disease in 5% of two of three cores and negative findings in remaining background cores. C, Follow-up MR image obtained 2.5 years after A and B shows increase in size of lesion to mm. PSA value at follow-up was 5.65 ng/ml. D, Follow-up ADC map obtained 2.5 years after A and B shows reduction in ADC value to mm 2 /s. Repeat targeted biopsy revealed Gleason = 7 (10% Gleason pattern 4) in 80% of both cores. Patient underwent prostatectomy, and final pathology diagnosis was Gleason = 7, pt2cn0, and M0. B D MRI accuracy varies depending on the patient selection criteria, MRI sequences used, grade and volume of disease, and reader expertise [34 36], which underlines the importance of recent attempts to standardize MRI acquisition and interpretation [37]. The negative predictive value of MRI for the presence of significant disease considered unsuitable for AS is consistently reported to be more than 90% and to even approach 100% depending on the definitions used [35, 38, 39]. However, some tumors remain occult on MRI even on retrospective evaluation because of a sparse growth pattern and a low malignant epithelium-stroma ratio [40 42]. MRI is known to lack sensitivity for identifying low-volume Gleason disease [38]; therefore, it is not surprising that negative MRI findings have been shown to be a good predictor of suitability for AS enrollment [37, 43, 44]. Likewise, if MRI findings are considered to be positive but concordant with the nature of disease shown on the initial biopsy, then a second standard biopsy shows a low reclassification rate [45, 46]. Concordance is typically defined as an MRI abnormality matching the biopsy results in terms of location and likely volume [46]. A positive MRI result, particularly if discordant with the initial biopsy result, is typically seen as a trigger for a repeat biopsy ideally, a targeted biopsy. Although the criteria vary between studies, most studies use a Likert-based system that is often based on Prostate Imaging Reporting and Data System (PI-RADS) descriptors [37] in which a score of 3 of 5 is considered positive. A discordant result is one in which MRI shows a lesion in a sextant negative at systematic TRUS-guided biopsy or in a region not sampled systematically for example, the anterior gland 17 mm (the average core length) from the rectal wall [37] or the extreme apex. The positive predictive value of MRI for high-risk disease in these cohorts tends to be relatively low, in the order of 40 50% [46 49]. This low positive predictive value may reflect reader bias in prospective AS cohorts who are known to have a diagnosis of prostate cancer but are less likely to harbor large-volume posterior disease, resulting in false-positive overcalls [50]. In patients with an MRI-positive lesion, subsequent targeted biopsy upgrades patient risk in 40 60% of cases [51 53]. There is also a correlation to MRI suspicion, with high-probability targets 3 times more likely to result in upgrading and reclassification rates in these cases approaching 100% [45, 52]. AJR:208, January

4 Barrett and Haider Disease Progression in Patients on Active Surveillance The aim of AS is to delay the initiation of curative treatment; therefore, disease progression should not be seen as a failure of AS but rather as its natural consequence [54]. Approximately one-third of AS patients progress to active treatment with a median time of 2.5 years [55, 56]. The most relevant oncologic endpoints assessed are overall survival, cancer-related survival, and metastasis-free survival. However, these data are challenging to obtain given that the estimated 20-year mortality of patients on AS is only 2 3% [57] and that even the longest-running cohorts have not yet reached this time point [58]. Furthermore, the longest running of these series report on patients undergoing expectant management before the concept of AS had even been invented and before the application of strict enrollment and follow-up criteria, which brings a risk of retrospective allocation bias [59]. In the absence of long-term data, there is a lack of consensus about the best surrogate for establishing progression, and clearly estimating the number of patients with disease that will progress is highly sensitive to the definition chosen [55]. The criteria used include no longer meeting AS enrollment criteria, detection of higher-volume cancer or higher-grade cancer on follow-up biopsy, PSA value doubling time of less than 3 years, progression to radical treatment, or unequivocal clinical progression. Reclassification to disease no longer suitable for AS is inherently dependent on the AS selection criteria, and candidates no longer meeting the conditions of one AS program may still fall within the acceptable boundaries of another. Reliance on pathologic surrogates of either disease grade or volume risks encountering the sampling bias and reclassification errors already mentioned. Furthermore, pathology reporting may lack consistency, there may be intraand interreader discrepancies, and training and relative experience will influence interobserver agreement [60, 61]. In 2005, the International Society of Urological Pathology (ISUP) changed the Gleason grading system for prostate cancer, with recommendations trending toward the reporting of higher grades than before [62]. Independent of this change, studies have also shown that there may be a tendency, over time, for the same histopathologists to assign higher grades to the exact same biopsy specimens [63]. Therefore, patients on longer-term follow-up with a tumor previously diagnosed as Gleason score 6 at enrollment and unchanged may now be considered Gleason score 7 on contemporary interpretation. Radical treatment as a primary outcome measure for AS will represent a selection bias and will also include patients who have chosen treatment, which is often because of the psychologic burden of living with cancer rather than to the true biologic progression of disease [64]. A C D Fig. 3 At follow-up of prostate cancer patient undergoing active surveillance (AS), conspicuity of lesion on MRI is reduced, and Prostate Imaging Reporting and Data System (PI-RADS) score is lower. In this example, patient is 71-year-old man with initial prostate-specific antigen value of 3.4 ng/ml. A, Baseline T2-weighted MR image shows focal area of low signal intensity at left apex peripheral zone (PZ) (arrow). PI-RADS score for baseline T2-weighted imaging was 3. B, Baseline apparent diffusion coefficient (ADC) map shows mild focal restricted diffusion (arrow) corresponding to lesion shown in A. PI-RADS score for baseline DWI was 4. Targeted biopsy of left mid and apex PZ at baseline showed Gleason = 6 in one of three cores with less than 5% involvement. C, Follow-up T2-weighted MR image obtained 1 year after A and B shows conspicuity of lesion (arrow) is reduced compared with baseline. PSA value at follow-up was 2.4 ng/ml. PI-RADS score for follow-up T2-weighted imaging was 2. D, Follow-up ADC map obtained 1 year after A and B shows more geographic appearing intermediate-signalintensity lesion (arrow) and less convincing restricted diffusion than baseline DW image. PI-RADS score for follow-up DWI was 2. Patient remained on AS. MRI for Follow-Up of Patients in Active Surveillance Programs MRI may be able to supplement decision making in AS follow-up given the challenges in defining progression from a clinicopathologic perspective. TRUS-guided biopsy is associated with a complication rate of approximately 10% [65]; therefore, avoiding the routine 1-year follow-up biopsy in patients with MRI-stable disease could confer a significant health care advantage. Indeed, recent versions of some national guidelines allow MRI to supplement or replace repeat biopsy in patients with biochemical results concerning for progression (i.e., rising PSA values, rising PSA density values, or short PSA doubling time) or in patients with a discordance between baseline pathology results and subsequent course [10, 66]. It is important to state that the role of MRI in the followup setting is to detect significant cancer that B 134 AJR:208, January 2017

5 Role of MRI in AS of Prostate Cancer will prompt a change from AS to active treatment rather than identifying any cancer as in the detection phase [33]. Toward this end, one of the key challenges is to define what constitutes radiologic progression on MRI (Appendix 2). Considerations include anatomic features such as a change in size or stage (Fig. 2), functional characteristics including DWI and dynamic contrast-enhanced MRI (DCE-MRI) parameters, or a combination of findings relating to lesion conspicuity as reflected by PI-RADS scoring (Fig. 3). The appearance of new lesions (Fig. 4) or an increase in TNM staging on MRI is clear evidence of progression; however, significant change in an existing lesion may be harder to define. For consistency, lesion size should be measured in the same imaging plane; in addition, in accordance with the updated PI-RADS guidance, lesions in the peripheral zone should be measured on apparent diffusion coefficient (ADC) maps and lesions in the transition zone on T2-weighted images or, if compromised, on the most conspicuous sequence [67]. Low-volume low-grade disease that is appropriate for AS is often MRI-occult, which makes lesion comparisons impossible. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria used to define tumor progression can only be applied for measurable lesions 10 mm [68], and even MRI-concordant lesions deemed suitable for AS often do not reach that size threshold. Some authors have set the lesion diameter cutoff for defining significant disease on either anatomic imaging or DWI at 10 mm [46, 69]. ADC values have been shown to correlate inversely to Gleason grade [70 72]; thus, a change in functional MRI parameters offers potential as a surrogate marker of progression. The Choi criteria use the functional surrogate of CT density in gastrointestinal stromal tumors [73]; however, attenuation (measured in Hounsfield units) is a more reliable and robust measurement than functional parameters derived from MRI. It is known that ADC values can vary up to 20% on repeat abdominal imaging in the same patients [74]. It is therefore difficult to determine a change that could be considered significant enough to warrant the designation of progression on imaging. Morgan et al. [24] showed that a reduction in the whole-gland ADC value of > 10% was associated with progression to radical treatment but that nonprogressors also showed a less marked decrease in ADC values. Likewise, DCE-MRI derived permeability parameters show considerable inter- and intraobserver variability and are dependent on both the pharmacokinetic modeling selected and the software used [75, 76]. However, permeability parameters are rarely reported in the clinical setting, and a more simplistic measure such as a change in DCE-MRI curve type might be able to serve as a marker of progression on MRI. Regardless of whether a threshold is set or the rate of change in lesion volume or in functional measurements is considered, MRI evidence of disease progression should be considered a trigger for repeat biopsy (ideally, a targeted biopsy) rather than immediate initiation of active treatment [15]. Decisions will also need to be considered in light of clinical features and the patient s comorbidity and preferences before choosing an intervention [33]. A C Future Roles of MRI Prostate cancer specific survival has recently been shown to be very good in two series with long-term follow-up of more than 15 years. In particular, the Johns Hopkins Hospital series [77], which had stringent entrance criteria to study patients with a low-risk profile, has shown a 99.9% disease-specific survival, and the University of Toronto cohort has shown 94.3% survival [58]. These results suggest that the role of MRI in changing survival outcomes in patients with low-risk disease may be limited and that the real value of MRI may be in an improved quality of life through fewer biopsies and more confidence in entering more patients in AS programs. It is estimated that more than half of patients with low-risk disease suitable for AS Fig. 4 Disease progression on active surveillance (AS). In this example, new lesion was detected in 52-yearold man with prostate-specific antigen (PSA) value of 3.86 ng/ml at baseline and PSA value of 3.6 ng/ml at 2 years. Initial transrectal ultrasound guided biopsy showed Gleason disease in 2% of one of six right-sided cores. A and B, Baseline MR images. No lesion was identified on baseline MR images. C, Follow-up axial T2-weighted MR image obtained 2 years after A and B shows new lesion (asterisk) in left apex peripheral zone. D, Follow-up apparent diffusion coefficient (ADC) map obtained 2 years after A and B. shows restricted diffusion in new lesion (asterisk) in left apex peripheral zone. Subsequent targeted biopsy confirmed Gleason disease, and patient underwent active treatment with radiotherapy. B D AJR:208, January

6 Barrett and Haider will undergo initial radical treatment [78, 79]. Clearly more stringent enrollment criteria will limit the number of eligible men; however, there remains a significant variation in practice between centers with AS as a management option for prostate cancer (all Gleason grades) ranging from 0% to 28% [80]. Potential barriers to the selection of AS may include patient or clinician preference, cultural bias for treatment, medicolegal risk, or a relative lack of economic reimbursement [80, 81]. MRI may help to address some of these issues such as a lack of faith from clinicians in TRUS-guided biopsy derived pathology results and may help to minimize the invasive nature of follow-up. Indeed, experience at University College London, with the follow-up of indeterminate lesions (Likert 3/5) by sequential multiparametric MRI, suggests that patients are willing to undergo repeated multiparametric MRI studies performed without an endorectal coil to avoid one biopsy (Puwani S, oral communication, 2015). Beyond this role, MRI findings may provide the confidence to expand the inclusion criteria for AS in terms of verifying volume or grade of disease detected at biopsy. The results of a large multicenter retrospective analysis suggest that more than half of patients with Gleason disease have characteristics suitable for AS enrollment [82]. Gondo et al. [83] recently showed that MRI may help to identify this subgroup of patients with low-volume Gleason disease: They found that the absence of a dominant prostate tumor on combined T2-weighted imaging and DWI was a significant predictor of Gleason downgrading at subsequent prostatectomy. There are several reasons why pathology results from needle biopsy may not concur with final pathology results at prostatectomy, including sampling error, reader error, and borderline grades. In addition, approximately 20% of radical prostatectomy specimens are known to contain tertiary patterns of Gleason grade, which can be sampled at biopsy and can result in an apparent overgrading on needle biopsy [84] (Appendix 3). This possible overgrading may be a particular risk in the context of targeted biopsy because the most radiologically suspicious area of a lesion can be oversampled. Theoretically, patients with as little as 1% grade 4 disease and patients with as much as 49% grade 4 disease will be classified as having Gleason disease, but these cases have clear potential to behave differently even when allowing for sampling error. Toward this end, the ISUP is discussing the routine reporting of grade 4 percentage to aid this distinction [85]. MRI may help to expand the criteria for AS to include Gleason disease in the context of negative or biopsy-concordant MRI findings and particularly in the context of patients with no additional clinicopathologic risk factors [82, 86]. Summary AS has emerged as an important management strategy to avoid overtreatment of low-risk indolent prostate cancer. It is likely that current urologic practice will serve to increase the number of patients diagnosed with prostate cancer suitable for AS by performing repeated PSA testing, using a lower PSA threshold for prostatic biopsy, obtaining more cores at biopsy, and repeating a biopsy after initial negative results [55]. Concomitantly MRI has emerged as an important diagnostic tool for the localization and characterization of prostate tumors and has an increasing role to play in both the selection and follow-up of AS candidates. However, the incorporation of MRI into AS protocols is a relatively new concept and has resulted in series with only short follow-up to date. MRI has been shown to have a high negative predictive value for ruling out clinically significant cancer; conversely, positive MRI findings concordant with the initial biopsy have a low reclassification rate. The key role of multiparametric MRI in AS is therefore in reducing the baseline inclusion of patients with unfavorable pathologic patterns of disease. It is likely that MRI will also be used as a means of broadening inclusion criteria to incorporate patients with Gleason disease and clinicopathologic features considered favorable for AS. Stable appearances on follow-up MRI may also help reduce the need for repeat biopsy in a proportion of patients, whereas a change on follow-up MRI should be seen as a trigger for repeat biopsy ideally, targeted biopsy rather than as a trigger for a move to active treatment. The main issues surrounding MRI and AS are the heterogeneity of inclusion criteria, the definition of significant disease, and agreement on what constitutes both radiologic progression and clinical progression. Thus, the timing and frequency of MRI in follow-up and indeed its cost-effectiveness are yet to be defined. Prospective cohorts with MRI at enrollment and long-term follow-up are required to further address these challenges. References 1. Maddams J, Utley M, Møller H. Projections of cancer prevalence in the United Kingdom, Br J Cancer 2012; 107: Etzioni R, Tsodikov A, Mariotto A, et al. Quantifying the role of PSA screening in the US prostate cancer mortality decline. Cancer Causes Control 2008; 19: Welch HG, Albertsen PC. Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening: J Natl Cancer Inst 2009; 101: Rietbergen JB, Hoedemaeker RF, Kruger AE, Kirkels WJ, Schröder FH. 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9 Role of MRI in AS of Prostate Cancer APPENDIX 1: Challenges of Active Surveillance (AS) as a Management Strategy for Prostate Cancer Challenges Defining significant disease. Heterogeneity of inclusion criteria between centers. Less than 50% of patients who are eligible for AS actually enroll in AS programs. Early reclassification rate of 20 30% reflects poor patient selection. Long-term follow-up is needed to show overall survival and disease-free survival. Pathology Issues Whole-gland imaging overcomes sampling bias. Whole-gland imaging provides accurate measurements of tumor volume. Whole-gland volumes allow accurate prostate-specific antigen density measurements. MRI provides information about local and locoregional staging. Functional assessments can correlate to tumor aggressiveness. MRI has a high negative predictive value for significant disease. Negative MRI findings or MRI findings that are concordant with transrectal ultrasound guided biopsy result in low rates of reclassification. MRI is minimally invasive (an endorectal coil typically is not used for follow-up). MRI findings can reduce the number of biopsy cores (target cores only) needed or can avoid the need for follow-up biopsy. Retrospective allocation bias for earliest cohorts on expectant management. Lack of consensus about the best surrogates for defining progression. Retrospective allocation bias when assessing surrogate measures of progression. APPENDIX 2: Advantages and Challenges of Using MRI in Active Surveillance (AS) Programs Advantages Whole-gland imaging overcomes sampling bias. Whole-gland imaging provides accurate measurements of tumor volume. Whole-gland volumes allow accurate prostate-specific antigen density measurements. MRI provides information about local and locoregional staging. Functional assessments can correlate to tumor aggressiveness. MRI has a high negative predictive value for significant disease. Negative MRI findings or MRI findings that are concordant with transrectal ultrasound guided biopsy result in low rates of reclassification. MRI is minimally invasive (an endorectal coil typically is not used for follow-up). MRI findings can reduce the number of biopsy cores (target cores only) needed or can avoid the need for follow-up biopsy. Potential to help expand inclusion criteria for AS (i.e., low-volume Gleason grade 4 disease). APPENDIX 3: Pathology Issues Related to Active Surveillance (AS) Challenges MRI at Enrollment Defining radiologic significant disease. MRI acquisition and interpretation require standardization. Low 40 50% positive predictive value for high-risk disease in AS cohorts reflects overcalling. MRI at Follow-Up Defining radiologic progression: Lesions often do not meet Response Evaluation Criteria in Solid Tumors (RECIST)-measureable disease criteria. Using size thresholds versus rate of change. Functional measures suffer from poor repeatability and reproducibility. The use of MRI in AS is new, so prospective studies and longterm data are lacking. Can MRI be used to avoid or minimize follow-up biopsy? Can MRI be used to expand AS inclusion criteria? Potential to help expand inclusion criteria for AS (i.e., low-volume Gleason grade 4 disease). Transrectal ultrasound guided biopsy underestimates Gleason grade in one-third of cases and underestimates volume in onehalf of cases. Intrareader discrepancy with a trend to up-grade biopsy specimens compared with previous practice. Interreader discrepancies relating to experience and subspecialization. Changes to the Gleason grading system over the past 10 years may lead to artificial reclassification of patients on longer-term AS follow-up. Approximately 20% of prostates contain tertiary Gleason grades, which may be oversampled at targeted biopsy and may lead to overgrading. AJR:208, January