Prevalence of low-risk prostate cancer has increased because of

ORIGINAL ARTICLE Value of 3-T Multiparametric Magnetic Resonance Imaging and Magnetic ResonanceYGuided Biopsy for Early Risk Restratification in Acti...
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ORIGINAL ARTICLE

Value of 3-T Multiparametric Magnetic Resonance Imaging and Magnetic ResonanceYGuided Biopsy for Early Risk Restratification in Active Surveillance of Low-Risk Prostate Cancer A Prospective Multicenter Cohort Study Caroline M.A. Hoeks, MD, PhD,* Diederik M. Somford, MD, PhD,Þþ Inge M. van Oort, MD, PhD,Þ Henk Vergunst, MD, PhD,þ Jorg R. Oddens, MD,§ Geert A. Smits, MD,|| Monique J. Roobol, PhD,¶ Meelan Bul, MD, PhD,¶ Thomas Hambrock, MD, PhD,* J. Alfred Witjes, MD, PhD,Þ Jurgen J. Fu¨tterer, MD, PhD,* Christina A. Hulsbergen-van de Kaa, MD, PhD,# and Jelle O. Barentsz, MD, PhD*

Objectives: The objective of this study was to evaluate the role of 3-T multiparametric magnetic resonance imaging (MP-MRI) and magnetic resonanceYguided biopsy (MRGB) in early risk restratification of patients on active surveillance at 3 and 12 months of follow-up. Materials and Methods: Within 4 hospitals participating in a large active surveillance trial, a side study was initiated. Pelvic magnetic resonance imaging, prostate MP-MRI, and MRGB were performed at 3 and 12 months (latter prostate MP-MRI and MRGB only) after prostate cancer diagnosis in 1 of the 4 participating hospitals. Cancer-suspicious regions (CSRs) were defined on prostate MP-MRI using Prostate Imaging Reporting And Data System (PI-RADS) scores. Risk restratification criteria for active surveillance discontinuance were (1) histopathologically proven magnetic resonance imaging suspicion of node/bone metastases and/or (2) a Gleason growth pattern (GGP) 4 and/or 5 and/or cancer multifocality (Q3 foci) in MRGB specimens of a CSR on MP-MRI. Results: From 2009 to 2012, a total of 64 of 82 patients were consecutively and prospectively included and underwent MP-MRI and a subsequent MRGB. At 3 and 12 months of follow-up, 14% (9/64) and 10% (3/30) of the patients were risk-restratified on the basis of MP-MRI and MRGB. An overall CSR PI-RADS score of 1 or 2 had a negative predictive value of 84% (38/45) for detection of any prostate cancer and 100% (45/45) for detection of a GGP 4 or 5 containing cancer upon MRGB, respectively. A CSR PI-RADS score of 4 or higher had a sensitivity of 92% (11/12) for detection of a GGP 4 or 5 containing cancer upon MRGB. Conclusions: Application of MP-MRI and MRGB in active surveillance may contribute in early identification of patients with GGP 4 or 5 containing cancers at 3 months of follow-up. If, during further follow-up, a PI-RADS score of 1 or 2 continues to have a negative predictive value for GGP 4 or 5 containing cancers, a PI-RADS standardized reported MP-MRI may be a promising tool for the selection of prostate cancer patients suitable for active surveillance. Key Words: active surveillance, magnetic resonance imaging, MR-guided biopsy, prostate cancer (Invest Radiol 2014;49: 165Y172) Received for publication July 13, 2013; and accepted for publication, after revision, September 17, 2013. From the Departments of *Radiology, and †Urology, Radboud University Nijmegen Medical Centre; ‡Department of Urology, Canisius Wilhelmina Hospital, Nijmegen; §Department of Urology, Jeroen Bosch Hospital, Den Bosch; ||Department of Urology, Alysis Zorggroep, Arnhem; ¶Department of Urology, Erasmus University Medical Centre, Rottterdam; and #Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Conflicts of interest and sources of funding: Supported by a Dutch Cancer Society Grant (KUN 2007-3971). The authors report no conflicts of interest. Reprints: Caroline M.A. Hoeks, MD, PhD, Department of Radiology, Meander Medical Centre, Amersfoort, PO Box 1502, 3800 BM Amersfoort, The Netherlands. E-mail: [email protected]. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0020-9996/14/4903Y0165

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P

revalence of low-risk prostate cancer has increased because of widespread prostate-specific antigen (PSA) testing.1 Patients with low-risk prostate cancer (Table 1) are prone to overtreatment and its complications, which can undermine a patient’s quality of life.1,2 To avoid overtreatment, active surveillance (AS) is an accepted treatment alternative for patients with low-risk prostate cancer.3 In general, a PSA of 10 ng/mL or less, a PSA density lesser than 0.15 ng/mL, clinical stages T1 to T2a, a Gleason score (GS) of 6 or lower without a Gleason growth pattern (GGP) 4 or 5, and 33% of cancer-positive transrectal ultrasound biopsy (TRUS-Bx) cores or less with 50 volume-percent of cancer per core or less are used as criteria to identify patients with low-risk cancer for inclusion in AS protocols.4 However, because of differences in the latter definition between different study protocols, a patient’s eligibility for AS may vary considerably (4%Y82%) between studies.5 Active surveillance is a management option that applies to patients with presumed low-risk prostate cancer, who are followed by regular PSA measurements, digital rectal examinations, and annually repeated systematic TRUS-Bx. In general, PSA kinetics, upgrading to a higher GGP (4 or 5), and volume progression are used as criteria for disease progression.4 However, because of TRUS-Bx undersampling upon inclusion rather than of true cancer progression, 20% to 30% of AS patients harbor cancers containing a GGP 4 or 5 or a cancer with a volume greater than 0.5 mL.4,6,7 Early identification of these patients, who were incorrectly considered suitable for AS, may be essential to maintain the opportunity for appropriate curative treatment. The detection of a GGP 4 or 5 and/or a larger cancer volume and/or multifocality of a GS of 3 + 3 cancer or less7 results in restratification of these prostate cancer patients into a higher risk category. Risk restratification implies discontinuation of AS and conversion to radical treatment. Magnetic resonanceYguided biopsy (MRGB) has shown to improve identification of patients having cancers with a GGP 4 or 5 because of a better highest GGP concordance (88%) with radical prostatectomy specimens compared with TRUS-Bx (55%, P = 0.001).8 The latter is caused by better localization and targeting of the most aggressive area of a cancer-suspicous region (CSR) on diffusion-weighted magnetic resonance imaging (MRI).8Y10 Only a few studies have related MRI results to AS outcome.11Y14 To our knowledge, MRGB has not previously been evaluated at AS inclusion. Our hypothesis was that combined multiparametric MRI (MP-MRI) and MRGB may improve current TRUS-BxYbased selection of patients for AS by early detection of patients harboring cancers of a larger volume or cancers containing a higher GGP. Therefore, our purpose was to evaluate the value of 3-T MP-MRI and MRGB for early risk restratification of patients on AS at 3 and at 12 months of follow-up. www.investigativeradiology.com

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TABLE 1. Parameters of MP-MRI and MRGB

Protocol

Sequence

TR, ms

Flip Slice Angle, Thickness, Field of View, TE, ms degrees mm mm  mm

Multiparametric MRI lymph nodes and bone structures 3D T2WI TSE coronal 1390 100 100 T1WI TSE coronal 500 11 120 WBDWI EPI 6500 71 n.a. WBDWI EPI 6200 66 n.a. Endorectal multiparametric MRI local prostate T2WI Axial (TSE) 4280 99 120 Coronal 3590 98 120 Sagittal 4290 98 120 DWI SSEPI Axial 2600 90 n.a. PD GE Axial 3D 800 1.51 14 DCE-MRI Spoiled GE axial 3D 36 1.4 10 MR-guided biopsy T2WI TSE axial 3620 103 120 DWI EPI axial 3300 60 n.a. SSFP GE axial and sagittal 4.48 2.24 70

Matrix Size

Voxel Size, mm  mm  mm

b-Values, s/mm2

Temporal Resolution, s

1.0 3.0 3.0 3.0

320  384  385  385 

320 384 385 385

320  320 320  256 154  154 154  154

1.0 1.5 2.5 2.5

 1.0   1.5   2.5   2.5 

1.0 3.0 3.0 3.0

n.a. n.a. 600 50

n.a. n.a. n.a. n.a.

3.0 3.0 3.0 3.0 3.0 3.0

180  192  192  204  192  192 

178 96 134 204 192 192

448  448 384  384 384  384 136  136 128  128 128  128

0.4 0.5 0.5 1.5 1.5 1.5

 0.4   0.5   0.5   1.5   1.5   1.5 

3.0 3.0 3.0 3.0 3.0 3.0

n.a. n.a. n.a. 0/50/500/800 n.a. n.a.

n.a. n.a. n.a. n.a. n.a. 3.4

4.0 3.6 3.0

256  256 260  211 280  280

320  320 160  120 256  256

0.8  0.8  4.0 2.2  1.6  3.6 1.1  1.1  3.0

n.a. 0/100/400/800 n.a.

n.a. n.a. n.a.

3D indicates 3-dimensional; DCE-MRI, dynamic contrast-enhanced magnetic resonance imaging; DWI, diffusion-weighted magnetic resonance imaging; EPI, echo-planar imaging sequence; GE, gradient echo; MR, magnetic resonance; n.a., not applicable; PD, proton density weighted imaging; SSEPI, single-shot echo-planar imaging; SSFP, steady-state free precession; T2WI, T2-weighted magnetic resonance imaging; TE, echo time; TR, repetition time; TSE, turbo-spin echo; WBDWI, whole-body diffusion weighted imaging sequence.

Part of our patient population has been reported earlier.15 The latter article describes the value of apparent diffusion coefficient (ADC) values of MRGB diffusion-weighted imaging (DWI) scans for prostate cancer differentiation in patients with prostate cancer on AS. The current study investigates the overall outcome of the incorporation of MP-MRI and MRGB in AS at both 3 and 12 months of follow-up and on its consequences for patient management.

MATERIALS AND METHODS Within 4 centers participating in a large AS trial (NTR1718, http://www.trialregister.nl), a prospective side study (NTR2006) was initiated in consecutively and prospectively included patients from August 2009 to March 2012. Informed consent from the patients was obtained for the study as well as for the side study, and institutional review boards of the participating hospitals approved our side study. Inclusion and exclusion criteria are depicted in Appendix 1. In our side study, the patients on AS underwent pelvic MRI and MP-MRI in the second month and MRGB in the third month after initial cancer diagnosis upon systematic TRUS-Bx (time-point zero). Initial systematic TRUS-Bx consisted of 9 to 10 cores sampling both the transition and peripheral zones. Multiparametric magnetic resonance imaging and MRGB were repeated at 12 months of follow-up. All initial and repeated MP-MRI examinations, all initial and repeated MRGB procedures, and, as will be further elaborated in the Follow-up section below, all repeated TRUS-Bx examinations were performed in one of the 4 centers.

Magnetic Resonance Imaging Pelvic MRI for lymph node and bone staging was followed by MP-MRI of the prostate, consisting of T2-weighted MRI, DWI, and dynamic contrast-enhanced imaging (DCE-MRI) according to the European Society of Uroradiology (ESUR) guidelines.16 Imaging was performed on a 3-T magnetic resonance (MR) system (Trio Tim; Siemens, Erlangen, Germany) using a pelvic phased array and an endorectal coil (Medrad, Pittsburgh, PA) filled with 40 mL of perfluorcarbon (Fomblin; Solvay-Solexis, Milan, Italy). The DCE-MRI was performed by initial acquisition of proton-density weighted images, followed by spoiled T1-weighted gradient echoes during fast (2.5 mL/s) intravenous injection 166

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of 0.1 mmol of gadoterate meglumine (Dotarem; Guerbet, Paris, France) per kilogram of body weight. Magnetic resonance imaging parameters are presented in Table 1.

Magnetic Resonance Imaging Interpretation An experienced radiologist (J.O.B.) with 19 years of experience in prostate MRI evaluated all MP-MRI examinations on in-houseY developed software while disposing of clinical patient data.17 Using the software, T2-weighted MRI, DWI, and DCE-MRI were interpreted simultaneously.17 The Prostate Imaging Reporting And Data System (PI-RADS) was used to define CSRs.16 Every CSR was scored on a 1-to-5Ypoint scale for T2-weighted MRI, DWI, and DCE-MRI separately. Subsequently, an overall 5-point score, based on the whole MP-MRI examination, was given for every CSR.16 The 5-point scale was defined as (1) highly unlikely, (2) unlikely, (3) equivocal, (4) likely, and (5) highly likely presence of clinically significant prostate cancer. Prostate cancer staging was performed in compliance with established criteria such as neurovascular bundle asymmetry, obliteration of the rectoprostatic angle, irregular bulging of the prostatic contour, tumor signal intensity within the periprostatic fat, and overt extracapsular tumor.18 When no CSR could be defined by MP-MRI, AS was continued without performing MRGB.

Magnetic ResonanceYGuided Prostate Biopsy All MRGB procedures were performed by an experienced radiologist (C.M.A.H.) with 3 years of experience in one of the 4 referral centers on the same MR scanner. This radiologist performed MRGB of every predefined CSR on a 3-T scanner in a separate examination session (MAGNETOM Skyra; Siemens, Erlangen, Germany).19 Magnetic resonanceYguided biopsy was performed for every CSR, regardless of CSR PI-RADS scores. Acquisition parameters are presented in Table 1. Earlier defined CSRs were re-identified on T2-weighted and diffusion-weighted MRI. An endorectally inserted needle guide was repositioned to aim at a CSR using sagittal and axial gradient echo sequences. Once needle guide positioning was adequate, biopsies were taken by inserting an 18-gauge needle biopsy gun (In vivo, * 2014 Lippincott Williams & Wilkins

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Schwerin, Germany) through the needle guide.19 Axial and sagittal gradient echo sequences were repeated, with the needle situated in the prostate, to confirm needle sampling of a CSR.

the foci in the initial TRUS-Bx. The latter criterion of cancer multifocality was applied to evaluate the number of additionally detected cancer foci by MRGB and to compare it with the TRUS-Bx risk restratification criterion of more than 2 cores with prostate cancer in the AS study.7 An MRGB focus located contralateral to the initial TRUS-Bx cancer location or a focus in the apex versus the base and vice versa was considered a separate cancer focus. Risk-restratified patients were no longer eligible for AS and were referred to undergo curative treatment. To evaluate cancer volume using MRGB and TRUS-Bx specimens, retrospectively, the maximal cancer core length (MCCL) was

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Risk Restratification at 3 Months of Follow-up Risk restratification, that is, stratification into a higher prostate cancer risk category, was based on (1) pelvic MRI suggestion of node/bone metastases of prostate cancer, which was histopathologically proven,20 or (2) MRGB histopathology specimens (of CSRs) containing (a) cancers with GS composed of a GGP20 4 or 5 or (b) multifocality of 3 or more foci GS of 3 + 3 cancer or lower, including

FIGURE 1. Study flow diagram showing patient selection. CSR indicates cancer suspicious region; MRI, magnetic resonance imaging; MP-MRI, multiparametric MR imaging; MRGB, MR guided prostate biopsy; MR, magnetic resonance; CSR, cancer suspicious region on magnetic resonance imaging; TRUS-Bx, systematic transrectal ultrasound biopsy. * 2014 Lippincott Williams & Wilkins

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measured. This was defined as the longest biopsy core specimen cancer core length taken from 1 CSR. An MCCL of 6 mm or longer is related to a cancer volume of 0.5 mL or greater in radical prostatectomy specimens using schematic mapping biopsy.21

Follow-up After 11 to 12 months of follow-up, repeated MP-MRI of the local prostate, with imaging parameters identical to those of the initial MP-MRI, was performed. On the basis of the repeated MP-MRI, an additional repeated MRGB, with indication and procedure similar to those of the initial MRGB, was performed in a second separate imaging session. After the repeated MRGB, a repeated TRUS-Bx session was performed on the same day by an experienced nurse practitioner, who was blinded to the initial and follow-up MP-MRI results. Repeated TRUS-Bx consisted of a schematic 10 core biopsy scheme, including sextant biopsy of the peripheral zone and 2 biopsies of the transition zone on both sides of the prostate. The TRUS-Bx risk restratification consisted of prostate cancer presence in more than 2 cores or a GS of 6 (3 + 3) or higher.7,21 Risk restratification criteria for repeated MP-MRI and repeated MRGB were according to the criteria as described previously.

Histopathology All biopsy samples were evaluated by 1 genitourinary pathologist (C.A.H.) with 20 years of experience, who was blinded to prior histopathology results. Gleason grading was performed according to the modified consensus22 of the International Society of Urological Pathology in 2005. Prostatitis was defined as the presence of intraprostatic inflammatory infiltrates.23

Statistical Analysis Patient risk restratification rates were determined for the initial (3 months) and repeated MRGB and for the repeated TRUS-Bx (12 months). Parametric continuous variables were reported as mean T 95% confidence interval, and nonparametric continuous variables were reported as median and the interquartile range (IQR). Receiver operating characteristic curves were applied to compare different MPMRI techniques using the area under the curve (Az). Analyses were performed using PASW Statistics version 18 (SPSS, Inc, Hong Kong, China). The threshold for significance was set at P G 0.05.

RESULTS Initial Risk Restratification (3 Months) Of the 82 AS patients, 66 patients were included in our side study and underwent MP-MRI. Two patients requested to be excluded from the protocol before MRGB, leaving 64 patients for the study. Patient selection is described in Figure 1. Patient characteristics of these 64 patients are shown in Table 2. One additional patient was excluded because of an MRI result suggestive of a bone metastasis in his third lumbar vertebra, which, upon biopsy, appeared to be a metastasis from malignancy of unknown origin. Magnetic resonanceYguided biopsy was performed in 62 of the 63 remaining patients. In 1 patient, MRGB was not performed because MP-MRI did not show a CSR and this patient continued AS. In the remaining 62 patients, a median of 2 (IQR, 1Y2) CSRs were identified with a median of 4 acquired MRGB cores (IQR, 3Y5) per patient. A patient example is illustrated in Figure 2. Fourteen percent (9/63) of the 63 patients were risk-restratified on the basis of MP-MRI and MRGB and thus underwent radical treatment on the basis of MRGB specimens containing cancers with a GGP 4 or 5 (n = 7) and/or 3 or more foci GS of 3+3 cancer or lower (n = 2). The MRGB and MCCL results are presented in Table 3. Six patients were lost to follow-up because diversion to radical treatment was not initiated according to the predefined criteria (based 168

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TABLE 2. Patient Characteristics of 64 MP-MRI Patients Characteristic Age, median (IQR), y PSA, mean (CI), ng/mL PSA density, mean (CI), ng/mL per mL Prostate volume, median (IQR), mL No. previous negative TRUS-Bx sessions, median (range) Total no. TRUS-Bx cores at diagnosis, median (IQR) TRUS-Bx to MRI interval, median (IQR), mo TRUS-Bx to MRGB interval, median (IQR), mo Characteristic Clinical stage T1c T2a T2b T2c Positive TRUS-Bx cores at diagnosis, 1 2 Gleason score at diagnosis, 3+3=6 Lower

All Included Patients (n = 64) 65.7 (62.1Y70.1) 6.5 (5.99Y6.93) 0.1 (0.12Y0.14) 45.8 (38.0Y66.1) 0 (0Y7) 10 (9Y10) 2.1 (1.6Y2.7) 2.7 (2.0Y3.3) All included patients no., percentage (fraction), [95% confidence interval] 76.6 (49/64), [64.8Y85.4] 18.8 (12/64), [10.9Y30.1] 3.1 (2/64), [0.2Y11.3] 1.6 (1/64), [0.0Y9.1]

67.2 (43/64), [55.0Y77.5] 32.8 (21/64), [22.5Y45.0] 93.8 (60/64), [84.6Y98.0] 6.3 (4/64), [2.0Y15.4]

AS indicates active surveillance; CI, 95% confidence interval; IQR, interquartile range; MP-MRI, multiparametric magnetic resonance imaging; MRGB, magnetic resonanceYguided prostate biopsy; PSA, prostate-specific antigen; TRUS-Bx, systematic transrectal ultrasound biopsy.

on only 2 foci GS 3+3 cancer [n = 4] or based on suspicion of extracapsular extension on MRI without confirmation of extracapsular extension on MR-guided biopsy [n = 2]). The remaining 48 patients continued AS. Eighteen of these patients had MRGB results according to our predefined AS criteria and 30 patients had a cancer-negative MRGB specimen.

Risk Restratification at 12 Months of Follow-up In 37 of the 48 remaining AS patients (77%), a follow-up of 12 months was available. Of these 37 patients, 7 patients did not undergo the repeated MP-MRI and MRGB examinations because of impossible repeated examinations caused by the following: shoulder injury (n = 1), pain after MRGB (n = 1), complications of chemotherapy for lymphoma (n = 2), or because of patient request (n = 3). Follow-up MRGB and MCCL results for the remaining 30 patients are presented in Table 4. Forty-seven percent of these follow-up patients (14/30) were risk-restratified on the basis of MRGB and/or TRUS-Bx. In 13% (4/30) of the patients, risk stratification was based on TRUS-Bx only; in 10% (3/30), on MRGB only and in 23% (7/30), on both modalities. At 12 months of follow-up, the application of MP-MRI and MRGB yielded an additional 10% (3/30) of risk-restratified patients missed by TRUS-Bx. The 14 risk-restratified patients at 12 months of follow-up were not identified earlier on the initial combined MP-MRI and MRGB. Retrospectively, in 4 of these patients, the CSR was detected on the initial MP-MRI, but the initial MRGB did not sample prostate tissue (n = 2) or missed small cancers (repeated MRGB MCCL * 2014 Lippincott Williams & Wilkins

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1.5Y2 mm) (n = 2). In the other 10 of the 14 patients, presumably, small lesions (G0.5 mL) may have not been scored on the initial MP-MRI (repeated MRGB MCCL, 0.3Y4.5 mm). For 14 of the 30 patients with an initial cancer-negative MRGB, repeated MP-MRI and repeated MRGB were available. The negative predictive value (NPV) of a cancer-negative MRGB for

risk restratification at repeated examinations was 79% ([11/14], 95% confidence interval, 52%Y93%).

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Results for MRI PI-RADS Scores The MP-MRI evaluation on both 3 and 12 months resulted in a total of 168 CSRs. Because this study started at early PI-RADS

FIGURE 2. A 61-year-old man on AS with a PSA level of 7.1 ng/mL, a PSA density of 0.19 ng/mL per mL, and a clinical stage T1C. This patient was diagnosed with a GS of 6 (3 þ 3) prostate cancer in 5 vol% in 1 of 12 cores in the right base of the peripheral zone. Multiparametric MRI and MRGB, consisting of 4 cores only, were performed within 3 months after the diagnosis. A, Axial T2-weighted turbo spin echo image (repetition time [TR], 4280 milliseconds; echo time [TE], 99 milliseconds): a low signal intensity with a lenticular shape and an erased charcoal sign (white arrows) is present in the ventral transition zone at the level of the mid-prostate. B, Axial ADC map of DWI (single-shot echo planar imaging; TR, 2600 milliseconds; TE, 90 milliseconds; b values, 0/50/500 and 800 s/mm2) at the level of the mid-prostate. A low ADC value of 0.50  10j3 mm2/s, suspicious for prostate cancer, was present on the right side of the ventral transition zone (dotted line). C, Axial overlay of Ktrans parameter in DCE-MRI (3-dimensional spoiled gradient echo; TR, 36 milliseconds; TE, 1.4 milliseconds; temporal resolution, 3.4 seconds), as calculated by the Tofts model, on the axial T2-weighted turbo spin echo image (TR, 4280 milliseconds; TE, 99 milliseconds). Areas of increased contrast enhancement are present in large parts of the prostate. Also, in the right ventral prostate (dotted line), increased enhancement is present. Enhancement in this region was suggestive of prostate cancer because of wash-out: a decline at the end of the relative gadolinium contrast-to-time curve (D), its location, and asymmetry. E, Axial angulated balanced gradient echo image (TR, 4.48 milliseconds; TE, 2.24 milliseconds) of the needle position in the lesion presented in A to C directly after the biopsy. The lesion (green dotted line) can be appreciated in the prostate (blue dotted line). The middle of the needle artifact is represented by a white line and is in the middle of the lesion. The needle guide (white arrows) is also depicted. The MRGB specimen (total of only 4 cores) contained a GS of 4 + 3 = 7 prostate cancer in 80 vol%. This patient’s management was subsequently redirected toward definitive therapy, which consisted of external beam radiotherapy. * 2014 Lippincott Williams & Wilkins

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TABLE 3. Reasons for Initial Patient Risk Restratification and Conversion to Treatment at 3 Months of Follow-up MRGB Results for Risk Restratified Patients

No.

MRGB GGP 4 or 5

7

MRGB multifocality Total of risk restratified patients, %†

2 9 (9/63 = 14%)

MRGB Core Specimen MCCL, Mean (95% Confidence Interval), mm* 10.6 (7.4Y13.7) Q6 mm: n = 6 4.0 (0.0Y7.9) Q6 mm: n = 1 Q6 mm: n = 7

The calculation of MRGB maximal cancer core length is based on the highest MRGB maximal cancer core length for every patient. *A biopsy core specimen maximal cancer core length of 6 mm or longer equals a prostate cancer volume of 0.5 mL or greater in radical prostatectomy specimens. †The total of 63 patients consists of the 62 patients undergoing magnetic resonanceYguided biopsy and 1 patient not undergoing magnetic resonanceY guided biopsy because of the lack of CSRs. GGP indicates Gleason grade pattern; GS, Gleason score; MCCL, maximal cancer core length; MP-MRI, multiparametric magnetic resonance imaging; MRGB, magnetic resonanceYguided prostate biopsy.

implementation, PI-RADS scores were available for 155 CSRs only. Overall, CSR PI-RADS scores at 3 and 12 months of follow-up are presented in Table 5. Seventy-eight percent (121/155) of the CSRs were located in the peripheral zone, 15% (23/155) were located in the transition zone, and 7% (11/155) were situated at the border of the peripheral and transition zones or seminal vesicles. The MRGB specimens showed cancer in 31% (48/155) of the CSRs. Cancer-negative MRGB specimens mainly contained prostatitis in 41% (44/107) and healthy prostate tissue in 38% (41/107). The Az values for the detection of any cancer prostate cancer and for the detection of a GGP 4 or 5 containing cancer, using overall PI-RADS scores, were 0.73 (0.65Y0.82) and 0.81 (0.70Y0.92), respectively.

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An overall CSR PI-RADS score of 1 or 2 had an NPV of 84% (38/45) for the detection of any cancer and an NPV of 100% (45/45) for the detection of a GGP 4 or 5 containing cancer upon MRGB. A CSR PI-RADS score of 4 or 5 had a sensitivity of 75% (36/48) and 92% (11/12) for the detection of, respectively, cancer and a GGP 4 or 5 containing cancer upon subsequent MRGB.

DISCUSSION The results of our side study show that, in an AS cohort, the initial application of MP-MRI and MRGB identifies patients with cancers containing higher GGPs (GGP 4 or 5), which were missed with TRUS-Bx in 14% (9/64). At 12 months of follow-up, MRGB further improves patient risk restratification rates compared with the repeated TRUS-Bx with another 10% (3/30). At 3 months of follow-up, our 11% rate of upgrading to a GGP 4 or 5 was lower compared with the 16% to 17% upgrading in 2 series reporting upon immediate repeated TRUS-guided biopsy after inclusion in an AS protocol.12,24 The higher rate of one of these series might be contributed to their overall population of patients with higher-risk prostate cancer because they considered patients with 3 or fewer cancer-positive cores eligible for AS.12 Also, it should be noted that we used less cores (a median of 4) in MRGB, compared with the 12-core immediate repeated TRUS-guided biopsy schemes in the mentioned series. At 12 months of follow-up, the results of the combined MP-MRI and MRGB diagnosed additional 3 patients for risk restratification, which were missed with TRUS-Bx and would therefore remain on AS. These were all caused by cancer multifocality. The overall risk restratification at 12 months of follow-up was based on a GGP 4 or 5 in 43% (6/14); increase in cancer volume (GS, e3 + 3), in 43% (6/14); cancer multifocality, in 36% (5/14). The detection of cancers with a GGP 4 or 5 up to 1 to 2 years after inclusion is assumed to be based on incorrect inclusion of cancers containing a higher GGP, rather than on actual tumor progression.6 Retrospectively, on the basis of our results so far, 13 patients with a cancer eventually containing a GGP 4 or 5 were incorrectly included in AS. At 3 months of follow-up, MP-MRI and MRGB did not identify 46% (6/13) of these patients, who were detected at 12 months of follow-up. A possible explanation for this can be deducted from Tables 3 and 4. At 3 months of follow-up, 6 of 7 cancers had an MCCL of 6 mm or longer

TABLE 4. Reasons for Patient Risk Restratification and Conversion to Treatment at Repeated Examinations at 12 Months of Follow-up Repeat MRGB Results for Risk-Restratified Patients

No.

MRGB MCCL, Mean (95% Confidence Interval), mm*

Both MRGB and TRUS-Bx GGP 4 and/or 5

4

MRGB GGP 4 and/or 5 and TRUS-Bx GS e3 + 3 cancer in 92 cores Only TRUS-Bx GGP 4 and/or 5 TRUS-Bx GS e3+3 cancer in 92 cores and MRGB multifocality

1 1 2

Only MRGB multifocality, (2 foci, n = 1)†

3

Only TRUS-Bx GS e3 + 3 cancer in 92 cores

3

5.3 (3.8Y6.8) Q6 mm: n = 2 4.4 (n.a.) 2.7 (n.a.) 6.5 (5.5Y7.5) Q6 mm: n = 2 4.2 (1.3Y7.0) Q6 mm: n = 1 5.7 (2.8Y8.6) Q6 mm: n = 1 5.0 (3.0Y6.0) Q6 mm: n = 6

Total (% of total repeated MRGB), n = 30

14 (47)

The calculation of MRGB maximal cancer core length is based on the highest MRGB maximal cancer core length for every patient. *A biopsy core specimen maximal cancer core length of 6 mm or longer equals a prostate cancer volume of 0.5 mL or greater in radical prostatectomy specimens. †Not conforming to the predefined risk restratification criteria. GGP indicates Gleason growth pattern; GS, Gleason score; MCCL, maximal cancer core length; MP-MRI, multiparametric magnetic resonance imaging; MRGB, magnetic resonanceYguided prostate biopsy; n.a., not applicable; TRUS-Bx, systematic transrectal ultrasound biopsy.

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& Volume 49, Number 3, March 2014

MRI and MR-Guided Biopsy in Active Surveillance

TABLE 5. Overall PI-RADS Scores for Cancer-Suspicious Regions at 3 and 12 Months of Follow-up Time Point (Months After Inclusion) 3 12 Total

PI-RADS1

PI-RADS 2

PI-RADS 3

PI-RADS 4

PI-RADS 5

Total

9 7 16

18 11 29

21 17 38

32 21 53

13 6 19

93 62 155

PI-RADS indicates Prostate Imaging Reporting And Data System.

corresponding to a tumor volume21 greater than 0.5 mL, whereas, at 12 months of follow-up, only 2 of 6 cancers had an MCCL of 6 mm or longer. Therefore, the smaller volume of the (higher GGP within these relatively small) tumors may have influenced missing 46% of GGP 4 or 5 containing cancers at 3 months of follow-up. A probably equally important finding as the early identification of aggressive cancer is the high NPV of MP-MRI and MRGB in AS, which may improve the selection of patients suitable for AS. Multiparametric magnetic resonance imaging had a sensitivity of 92% for the detection of GGP 4 or 5 containing cancers in case of higher PI-RADS scores (Q4) and an NPV of 100% for the detection of cancers containing a 4 or 5 GGP in case of PI-RADS scores 1 or 2. These results are comparable with those of Vargas et al,25 who reported an NPVof 96% to 100% and a sensitivity of 87% to 96% for biopsy upgrading in case of a predefined MR imaging score of 2 or less and 5 or higher for cancer presence. Furthermore, an initial cancer-negative MRGB specimen had an NPV of 79% for risk restratification at 12 months of follow-up. This finding may indicate that a cancer-negative initial MRGB may be a promising prognostic parameter for AS patient selection. Although our population is small and although our study was not designed to validate the PI-RADS scoring system, our results do show that standardized MP-MRI using PI-RADS is a promising technique for the differentiation between patients suitable for AS and patients with cancers containing a GGP 4 or 5, the latter needing radical treatment. These results may support reproducibility and reliability of our results on a larger scale. Our results for prostate cancer detection accuracy using MPMRI and MRGB in patients on AS are difficult to compare with those of the literature: other studies on MRI implementation in AS did not use MP-MRI and/or MRGB.11,13,14,26,27 Our Az values of 0.73 and 0.81 for the detection of any cancer and GGP 4 or 5 containing cancer were quite reasonable considering the expected prevalence of predominantly lower (GGP 2 to 3) comprising cancers in this selected AS patient population. Lower GGP containing cancers are known to have lower detection rates compared with cancers, which contain a higher GGP.28 Because our study is the first to evaluate MRGB in AS, we applied low threshold criteria for CSR determination on MP-MRI followed by biopsy of all CSRs, also including regions with low cancer suspicion (PI-RADS 1Y3). This resulted in a high number of patients (48%) with cancer-negative CSRs upon MRGB. With increasing MRI experience in AS patients, false-positive results may be reduced by increasing the biopsy threshold to a higher PI-RADS score. Limitations of the presented series are its small sample size and limited follow-up. Furthermore, because MP-MRI and MRGB are new techniques within AS, our risk restratification criteria may not have been optimal yet because they are partly based on existent criteria used for random systematic TRUS-Bx. The TRUS-Bx risk restratification criterion of the number of cancer-positive cores is designed to estimate total cancer volume using a random systematic biopsy technique. Magnetic resonanceYguided biopsy is a guided biopsy technique in which the latter criterion for tumor volume estimation cannot be applied. Moreover, MP-MRI prostate tumor volumetrics are not very accurate because tumor delineation is limited by false-positive (prostatitis, fibrosis) and false-negative (sparsely growing cancers and lower cancer GS) imaging results.29,30 Prostate * 2014 Lippincott Williams & Wilkins

cancer is a multifocal disease. Using MRGB, we acquired extra information on the amount and locations of prostate cancer foci; however, currently, we cannot effectively use this criterion because its prognostic value remains unknown. Another limitation might be that, although we used a structured semiobjective scoring system for MP-MRI readings, our readings were performed by a highly experienced radiologist, which may have limited the general applicability of our results. To perform prostate MP-MRI and MRGB, any center needs experience in performing both prostate MP-MRI and MRGB of the prostate. An important clinical implication of our study is that, upon application of MRI in AS patients, acquisition of histopathology of a CSR is required because of potential false-positive CSRs. Lack of histopathologic confirmation of a CSR may explain poor results for (MP-) MRI as a predictive tool for AS outcome in other studies.11,13,14,26,27 Currently, no other studies that incorporate both MP-MRI and MRGB at inclusion in AS protocols exist. Therefore, future research should focus on including both MP-MRI and MRGB in AS protocols for lowrisk prostate cancer. Other important subjects that warrant further investigation are the validation of MRGB in AS populations and the influence of the experience of the radiologist performing the MRGB procedure on the MRGB outcome. Magnetic resonanceYguided biopsy has not been applied earlier in patients on AS, who represent the lower part of the risk spectrum of patients with prostate cancer. Furthermore, in general, the effectiveness of any radiological procedure depends on the experience of the involved radiologist, and this statement probably also holds true for MRGB. In conclusion, the application of MP-MRI and MRGB in AS may contribute in early identification of patients with cancers containing a higher GGP (4 or 5) at 3 months of follow-up. If, during further follow-up, PI-RADS scores of 1 to 2 continue to have an NPV for cancers containing a GGP 4 or 5, standardized reported MP-MRI using PI-RADS may be a promising tool for the selection of patients suitable for AS. ACKNOWLEDGMENTS The authors thank Gijs de Lauw, nurse practitioner, for his contribution in the biopsy data acquisition. REFERENCES 1. Bangma CH, Roemeling S, Schroder FH. Overdiagnosis and overtreatment of early detected prostate cancer. World J Urol. 2007;25:3Y9. 2. Wei JT, Dunn RL, Sandler HM, et al. Comprehensive comparison of health-related quality of life after contemporary therapies for localized prostate cancer. J Clin Oncol. 2002;20:557Y566. 3. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012;367:203Y213. 4. Dall’Era MA, Cooperberg MR, Chan JM, et al. Active surveillance for earlystage prostate cancer: review of the current literature. Cancer. 2008;112: 1650Y1659. 5. Dall’Era MA, Albertsen PC, Bangma C, et al. Active surveillance for prostate cancer: a systematic review of the literature. Eur Urol. 2012;62:e95Ye106. 6. Duffield AS, Lee TK, Miyamato H, et al. Radical prostatectomy (RP) findings in patients who fail active surveillance of prostate cancer. Modern Pathol. 2009;22:749.

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7. Bul M, Zhu X, Valdagni R, et al. Active surveillance for low-risk prostate cancer worldwide: the PRIAS study. Eur Urol. 2013;63:597Y603. 8. Hambrock T, Hoeks C, Hulsbergen-van de KC, et al. Prospective assessment of prostate cancer aggressiveness using 3-T diffusion-weighted magnetic resonance imaging-guided biopsies versus a systematic 10-core transrectal ultrasound prostate biopsy cohort. Eur Urol. 2012;61:177Y184. 9. Maas MC, Futterer JJ, Scheenen TW. Quantitative evaluation of computed high b value diffusion-weighted magnetic resonance imaging of the prostate. Invest Radiol. 2013;48:779Y786. 10. Hoeks CM, Vos EK, Bomers JG, et al. Diffusion-weighted magnetic resonance imaging in the prostate transition zone: histopathological validation using magnetic resonance-guided biopsy specimens. Invest Radiol. 2013;48:693Y701. 11. Margel D, Yap SA, Lawrentschuk N, et al. Impact of multiparametric endorectal coil prostate magnetic resonance imaging on disease reclassification among active surveillance candidates: a prospective cohort study. J Urol. 2012;187: 1247Y1252. 12. Berglund RK, Masterson TA, Vora KC, et al. Pathological upgrading and up staging with immediate repeat biopsy in patients eligible for active surveillance. J Urol. 2008;180:1964Y1967. 13. Cabrera AR, Coakley FV, Westphalen AC, et al. Prostate cancer: is inapparent tumor at endorectal MR and MR spectroscopic imaging a favorable prognostic finding in patients who select active surveillance? Radiology. 2008;247: 444Y450. 14. Ploussard G, Xylinas E, Durand X, et al. Magnetic resonance imaging does not improve the prediction of misclassification of prostate cancer patients eligible for active surveillance when the most stringent selection criteria are based on the saturation biopsy scheme. BJU Int. 2011;108:513Y517. 15. Somford DM, Hoeks CM, Hulsbergen-van de Kaa CA, et al. Evaluation of diffusion-weighted MR imaging (DWI) at inclusion in an active surveillance protocol for low-risk prostate cancer. Invest Radiol. 2013;48:152Y157. 16. Barentsz JO, Richtenberg J, Clements R, et al. ESUR Prostate MR Guidelines 2012. Eur Radiol. 2012;22:746Y757. 17. Vos PC, Hambrock T, Barenstz JO, et al. Computer-assisted analysis of peripheral zone prostate lesions using T2-weighted and dynamic contrast enhanced T1weighted MRI. Phys Med Biol. 2010;55:1719Y1734. 18. Fu¨tterer JJ, Heijmink SW, Scheenen TW, et al. Prostate cancer: local staging at 3-T endorectal MR imagingVearly experience. Radiology. 2006;238:184Y191.

19. Hambrock T, Futterer JJ, Huisman HJ, et al. Thirty-two-channel coil 3T magnetic resonance-guided biopsies of prostate tumor suspicious regions identified on multimodality 3T magnetic resonance imaging: technique and feasibility. Invest Radiol. 2008;43:686Y694. 20. van den Bergh RC, Vasarainen H, van der Poel HG, et al. Short-term outcomes of the prospective multicentre ‘‘Prostate Cancer Research International: Active Surveillance’’ study. BJU Int. 2010;105:956Y962. 21. Ahmed HU, Hu Y, Carter T, et al. Characterizing clinically significant prostate cancer using template prostate mapping biopsy. J Urol. 2011;186:458Y464. 22. Epstein JI, Allsbrook WC Jr, Amin MB, et al. The 2005 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma. Am J Surg Pathol. 2005;29:1228Y1242. 23. Nickel JC, True LD, Krieger JN, et al. Consensus development of a histopathological classification system for chronic prostatic inflammation. BJU Int. 2001;87:797Y805. 24. King AC, Livermore A, Laurila TA, et al. Impact of immediate TRUS rebiopsy in a patient cohort considering active surveillance for favorable risk prostate cancer. Urol Oncol. 2013;31:739Y743. 25. Vargas HA, Akin O, Afaq A, et al. Magnetic resonance imaging for predicting prostate biopsy findings in patients considered for active surveillance of clinically low risk prostate cancer. J Urol. 2012;188:1732Y1738. 26. Guzzo TJ, Resnick MJ, Canter DJ, et al. Endorectal T2-weighted MRI does not differentiate between favorable and adverse pathologic features in men with prostate cancer who would qualify for active surveillance. Urol Oncol. 2012; 30:301Y305. 27. Fradet V, Kurhanewicz J, Cowan JE, et al. Prostate cancer managed with active surveillance: role of anatomic MR imaging and MR spectroscopic imaging. Radiology. 2010;256:176Y183. 28. Ikonen S, Karkkainen P, Kivisaari L, et al. Magnetic resonance imaging of prostatic cancer: does detection vary between high and low Gleason score tumors? Prostate. 2000;43:43Y48. 29. Schlemmer HP, Corvin S. Methods for volume assessment of prostate cancer. Eur Radiol. 2004;14:597Y606. 30. Langer DL, van der Kwast TH, Evans AJ, et al. Intermixed normal tissue within prostate cancer: effect on MR imaging measurements of apparent diffusion coefficient and T2Vsparse versus dense cancers. Radiology. 2008;249:900Y908.

APPENDIX 1. Active Surveillance Inclusion and Exclusion Criteria With an Additional Exclusion Criterion Used in Our Substudy Inclusion criteria Histopathologically proven adenocarcinoma of the prostate Men should be fit for curative treatment. PSA level at diagnosis e10.0 ng/mL PSA density G0.2 ng/mL per mL Clinical stage T1C or T2 Gleason score of e3 + 3 1 or 2 biopsy cores invaded with cancer Participants must be willing to attend the follow-up visits. Exclusion criteria Men who cannot or do not want to be operated or irradiated A former therapy for prostate cancer Additional exclusion criterion substudy Contraindications to MRI or to gadolinium-based contrast agents MRI indicates magnetic resonance imaging; PSA, prostate-specific antigen.

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