Imaging Characteristics of Prostate Cancer Patients Who Discontinued Active Surveillance on 3-T Multiparametric Prostate MRI

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1 Genitourinary Imaging Original Research Habibian et al. MRI for Active Surveillance of Prostate Cancer Genitourinary Imaging Original Research David J. Habibian 1 Corinne C. Liu 2 Alex Dao 1 Kaitlin E. Kosinski 1 Aaron E. Katz 1 Habibian DJ, Liu CC, Dao A, Kosinski KE, Katz AE Keywords: active surveillance, imaging, multiparametric MRI, progression, prostate cancer, tumor upgrading DOI: /AJR Received May 25, 2016; accepted after revision September 21, Based on a presentation at the American Society of Clinical Oncology 2015 annual meeting, San Francisco, CA. 1 Department of Urology, Winthrop University Hospital, Mineola, 1300 Franklin Ave, Ste ML6, Garden City, NY Address correspondence to A. E. Katz (akatz@winthrop.org). 2 Department of Radiology, Winthrop University Hospital, Mineola, NY. AJR 2017; 208: X/17/ American Roentgen Ray Society Imaging Characteristics of Prostate Cancer Patients Who Discontinued Active Surveillance on 3-T Multiparametric Prostate MRI OBJECTIVE. Early-stage prostate cancer may be followed with active surveillance to avoid overtreatment. Our institution s active surveillance regimen uses annual MRI in place of serial biopsies, and biopsies are performed only when clinically necessary. The objective of our study was to report the multiparametric MRI characteristics of prostate cancer patients who discontinued active surveillance at our institution after repeat imaging revealed possible evidence of tumor upgrading. MATERIALS AND METHODS. The Department of Urology at Winthrop University Hospital prospectively maintains a database of prostate cancer patients who are monitored with active surveillance. At the time of this study, there were 200 prostate cancer patients being monitored with active surveillance. Of those patients, 114 patients had an initial multiparametric MRI study that was performed before active surveillance started and at least one follow-up multiparametric MRI study that was performed after active surveillance began. The MRI findings were evaluated and correlated with pathology results, if available. RESULTS. Fourteen patients discontinued active surveillance because changes on follow-up MRI suggested progression of cancer. Follow-up MRI showed an enlarged or more prominent lesion compared with the appearance on a previous MRI in three (21.4%) patients, a new lesion or lesions suspicious for cancer in two (14.3%) patients, and findings suspicious for or confirming extracapsular extension in nine (64.3%) patients. Seven of the 14 (50.0%) patients had a biopsy after follow-up multiparametric MRI, and biopsy results led to tumor upgrading in six of the 14 (42.9%) patients. The duration of active surveillance ranged from 4 to 110 months. All patients received definitive treatment. CONCLUSION. The small number of patients with follow-up multiparametric MRI findings showing worsening disease supports the role of MRI in patients with early-stage prostate cancer. Multiparametric MRI is useful in monitoring patients on active surveillance and may identify patients with clinically significant cancer amenable to definitive treatment. S ince the introduction of the prostate-specific antigen (PSA) test as a biomarker for prostate cancer in 1991, there has been a marked increase in the detection and subsequent overtreatment of low-risk disease [1 3]. Prostate cancer is known to be slow growing for many of these men, and most malignancies diagnosed will remain clinically insignificant. With this information clinicians have recently developed an approach to monitor indolent disease and delay the need for definitive treatment, which may carry significant risk of genitourinary morbidity. This treatment option known as active surveillance has proved to be safe in men with early-stage prostate cancer for up to 15 years [4]. Nevertheless, there is no consensus about the opti- mal protocol for men being monitored with active surveillance. The typical active surveillance regimen closely monitors patients for signs of disease progression using serial PSA tests and annual biopsies. Our institution s active surveillance protocol uses digital rectal examination, regular PSA testing, and annual MRI in place of repeat biopsies. Currently there are many roles for MRI in the management and diagnosis of prostate cancer. The purpose of multiparametric MRI in patients on surveillance is to determine the risk and rates of progression while decreasing the complications and cost of unnecessary biopsies. Additionally, multiparametric MRI findings can aid in precise biopsy of suspicious lesions. In this study, our objective was to report the multiparametric MRI character- 564 AJR:208, March 2017

2 MRI for Active Surveillance of Prostate Cancer istics of prostate cancer patients who discontinued active surveillance at our single institution after repeat imaging revealed possible evidence of tumor upgrading. Materials and Methods Subjects The Department of Urology at Winthrop University Hospital maintains a database of prostate cancer patients who are monitored with active surveillance. From February 2002 to July 2015, there were 200 patients in the database, and 114 of these patients underwent an initial multiparametric MRI examination before starting active surveillance and had at least one follow-up multiparametric MRI examination after enrolling in active surveillance. The MRI findings of the patients who left the active surveillance program were evaluated and correlated with pathology results, if available. Demographic information and disease characteristics were recorded. MRI Technique At our institution, all prostate MRI examinations are performed using a 3-T MRI system (Intera Achieva 3 T TX, Philips Healthcare) equipped with a 6-channel coil (Cardiac SENSE, Philips Healthcare). After a localizer scan is obtained, axial, coronal, and sagittal T2-weighted fast spinecho and axial T1-weighted spin-echo sequences are acquired. DWI is acquired in the axial plane using a single-shot echo-planar imaging technique with parallel imaging and fat suppression (spectral inversion recovery). Diffusion-encoding gradients are applied as five b values ranging from 0 to 2000 s/mm 2 (0, 500, 1000, 1500, and 2000 s/mm 2 ) along the three orthogonal directions of motion-probing gradients. Apparent diffusion coefficent maps are automatically constructed on a pixel-by-pixel basis (b values from 0 to 2000 s/mm 2 ). Dynamic contrast-enhanced image stacks are obtained before and 10 seconds after the start of a contrast bolus injected at 2 ml/s; the bolus was either gadodiamide (0.5 mmol/kg of body weight [Omniscan, Amersham Health]) or gadoterate meglumine (0.1 mmol/kg of body weight [Dotarem, Guerbet]). TABLE 1: Demographic Characteristics and Tumor Characteristics of Prostate Cancer Patients on Active Surveillance Variable Results The median age of our cohort was 65 years old (interquartile range [IQR], years). The median time on active surveillance for the entire cohort was 48 months (IQR, months). The median time on active surveillance before receiving definitive treatment was 35 months (IQR, months). Table 1 lists the demographic information and tumor characteristics of the active surveillance cohort. Of the 114 patients with both an initial multiparametric MRI examination and at least one follow-up multiparametric MRI examination, active surveillance was discontinued in 14 (12.3%) patients because of changes on follow-up MRI suggesting progression of prostate cancer (Table 2). Nine (64.3%) repeat MRI examinations showed suspicious or frank extracapsular extension (Fig. 1), two (14.3%) depicted a new lesion suspicious for Value Men, no. (%) 200 (100) Age (y) Median (IQR) 65 (60 70) Time on active surveillance (mo) Median (IQR) 48 (36 68) Gleason score at initial biopsy, no. (%) of patients (75.0) (12.0) (2.5) Missing data 21 (10.5) Initial PSA value (ng/ml) Median (IQR) 4.0 ( ) No. of biopsy cores positive for cancer, no. (%) of patients 1 Core 87 (43.5) 2 Cores 41 (20.5) 3 Cores 22 (11.0) 4 Cores 21 (10.5) 5 Cores 2 (1.0) 6 Cores 5 (2.5) 7 Cores 0 (0) 8 Cores 1 (0.5) 9 Cores 1 (0.5) Missing data 20 (10.0) Highest affected cores, no. (%) of patients < 5% 38 (19.0) 5 10% 64 (32.0) 11 15% 11 (5.5) 16 20% 13 (6.5) 21 25% 5 (2.5) 26 30% 13 (6.5) 31 40% 13 (6.5) > 40% 20 (10.0) Missing data 23 (11.5) Note IQR = interquartile range, PSA = prostate-specific antigen. cancer (Fig. 2), and three (21.4%) MRI examinations revealed an enlarged or more prominent lesion (Fig. 3). Of these 14 patients, seven (50.0%) underwent rebiopsy after multiparametric MRI. Rebiopsy revealed tumor upgrading in six of these 14 (42.9%) men. Gleason 6 cancer was upgraded to Gleason 7 (3 + 4) in two patients and to Gleason 8 (4 + 4) in one patient. One AJR:208, March

3 patient whose initial biopsy showed prostatic intraepithelial neoplasm was found to have Gleason 7 (3 + 4) cancer on rebiopsy. Finally, the Gleason score between biopsies did not change in one man, but disease was upgraded because of an increase from four cores to nine cores positive and a percentage increase in tumor volume of from 20% to 80%. The results from the initial biopsy were missing in one patient; however, rebiopsy after abnormal multiparametric MRI findings revealed Gleason 7 (3 + 4) cancer in three cores. The remaining seven (50%) patients left active surveillance solely because of progression on MRI and opted to forego biopsy confirmation. Of the 14 patients who left active surveillance, 10 elected to undergo cryoablation, two received radiation therapy (Cyberknife, Accuray), and two patients underwent radical retropubic prostatectomy. Habibian et al. TABLE 2: MRI Findings in 144 Prostate Cancer Patients With Initial and Follow-Up MRI Studies Variable Value Patients with initial and follow-up MRI, no. (%) 144 (100.0) Patients who discontinued active surveillance because of follow-up 14 (10.0) MRI findings, no. (%) Time on active surveillance (mo) Median (IQR) 35 (20 53) Reason active surveillance was discontinued, no. (%) of patients Suspicion or confirmation of ECE 9 (64.3) Enlarged or more prominent lesion 3 (21.4) New lesion or lesions suspicious for cancer 2 (14.3) Note IQR = interquartile range, ECE = extracapsular extension. Discussion Determining a proper regimen in the detection and treatment of early-stage prostate cancer is of paramount concern for urologists. Recently, there has been controversy among clinicians surrounding the screening and overtreatment of prostate cancer. Men at risk for prostate cancer are currently identified and are evaluated using serum PSA tests. Numerous investigators have questioned the reliability of this biomarker because a PSA value may be elevated as a result of benign prostatic hyperplasia, inflammation, or infection. Annually, approximately 1 million prostate biopsies are performed in the United States and 80,000 90,000 in the United Kingdom, costing more than $2 billion per year [5, 6]. Prostate biopsies carry inherent risks of infection and sepsis and cause patient discomfort and anxiety [7, 8]. A study of the Medicare population revealed an increasing rate of hospitalization due to infectious complications after prostate biopsy in recent years, which may be attributable to increasing antimicrobial resistance [9]. Decreasing the number of unnecessary prostate biopsies would allow men to avoid these comorbidities while markedly decreasing health care costs [9 11]. Although transrectal ultrasound guided biopsy is considered the standard for the diagnosis of prostate cancer in high-risk men, the value of multiparametric MRI in the stratification of prostate cancer patients has been reported in several studies. In a study evaluating the effectiveness of MRI in the classification of prostate cancer before biopsy, suspicious MRI findings were significantly correlated with the presence of high-grade disease [12]. Another study found that multiparametric MRI findings in 133 patients were 93% sensitive and 92% accurate in predicting which patients were candidates for active surveillance [13]. Other studies have confirmed the usefulness of multiparametric MRI in predicting the progression of cancer [14, 15]. These studies suggest that multiparametric MRI has a role similar to the clinical-pathologic criteria such as the classification system proposed by D Amico [16] in determining which patients would be appropriate for active surveillance. Biopsies using fusion multiparametric MRI/ultrasound for guidance have recently gained popularity because studies evaluating the effectiveness of biopsies using MRI/ultrasound compared with the traditional cognitive-guided approach yielded promising results in the detection of clinically significant cancers [17 19]. Delongchamps et al. [18] reported that targeted biopsies using MRI/transrectal ultrasound image registration detected more clinically significant cancers (Gleason 7 or greater) than random biopsy alone. In a similar study, Siddiqui et al. [12] found that targeted biopsy diagnosed a nearly identical number of cancer cases as standard biopsy (461 and 469 cases, respectively); however, targeted biopsies detected 30% more highrisk cancers and 17% fewer low-risk cancers (p < and p = 0.002, respectively) [12]. A limitation of this study is the variability of upgraded Gleason scores from specimens provided via needle biopsy. Gleason scoring remains one of the most effective prognostic indicators in prostate cancer [20]. Tumor grading thus plays a pivotal role in the management of prostate cancer patients, particularly in those who undergo multiple biopsies that reveal tumor upgrading. Indeed, an issue urologists struggle with is the uncertainty of a patient s Gleason score because numerous studies have reported disparities between the Gleason score based on needle core biopsy and the Gleason score of the actual specimen after radical prostatectomy [21]. This discrepancy may result from biopsy sampling errors during systematic prostate biopsies. Furthermore, variation in Gleason scoring may be caused by differences in tumor evaluation between pathologists. This occurrence has been well documented since the revision of the Gleason scoring system by the International Society of Urological Pathology in 2005 and remains to be a problem to be addressed in clinical practice [22]. Visualization of the prostate on multiparametric MRI may allow clinicians to use an objective approach to identify changes or irregularities within the gland and avoid misclassification of tumor grade. The results of our study show the potential application of multiparametric MRI in prostate cancer patients being monitored with active surveillance. Our active surveillance regimen uses annual MRI rather than annual biopsy and only moves forward with biopsy when prompted with rising PSA values, abnormal DRE results, increased patient anxiety, or abnormal MRI findings. Currently, we suggest that active surveillance patients who have a new lesion, an enlarged or more prominent lesion, or extracapsular extension of the primary tumor on MRI undergo prostate biopsy or intervention depending on the severity of cancer growth observed on MRI. Conclusion The small number of patients in our study cohort with worsening disease on followup multiparametric MRI supports the role 566 AJR:208, March 2017

4 MRI for Active Surveillance of Prostate Cancer of MRI as a means to monitor disease progression in patients with early-stage prostate cancer. Multiparametric MRI may serve as a substitute for serial biopsies currently used in active surveillance regimens to reduce the rate of sepsis and infection and avoid patient discomfort associated with repeat biopsies. Further prospective studies including large cohort sample sizes are necessary to validate the role of multiparametric MRI in the management of prostate cancer patients. Acknowledgment We thank Michael Kongnyuy who helped revise our manuscript and respond to the reviewers comments. References 1. Potosky AL, Miller BA, Albertsen PC, et al. The role of increasing detection in the rising incidence of prostate cancer. JAMA 1995; 273: Catalona WJ, Smith DS, Ratliff TL, et al. Detection of organ-confined prostate cancer is increased through prostate-specific antigen based screening. JAMA 1993; 270: Jacobsen SJ, Katusic SK, Bergstralh EJ, et al. Incidence of prostate cancer diagnosis in the eras before and after serum prostate-specific antigen testing. JAMA 1995; 274: Klotz L, Vesprini D, Sethukavalan P, et al. Longterm follow-up of a large active surveillance cohort of patients with prostate cancer. J Clin Oncol 2015; 33: Technology Marketing Corporation website. Lack of national diagnosis, care plan spurs call for action: partnership of public and private sectors and academia, resembling coalition built around breast imaging, may bring about manogram. www. tmcnet.com/usubmit/2008/01/02/ htm. Published January 2, Accessed April 2, National Institute for Health and Clinical Excellence. Prostate cancer: diagnosis and treatment. National Institute for Health and Clinical Excellence, Accessed October 25, Özden E, Bostanci Y, Yakupoglu KY, et al. Incidence of acute prostatitis caused by extended spectrum beta-lactamase-producing Escherichia coli after transrectal prostate biopsy. Urology 2009; 74: Dale W, Bilir P, Han M, Meltzer D. The role of anxiety in prostate carcinoma: a structured review of the literature. Cancer 2005; 104: Loeb S, Carter HB, Berndt S, Ricker W, Schaeffer EM. Complications after prostate biopsy: data from SEER-Medicare. J Urol 2011; 186: Nam R, Saskin R, Lee Y, et al. Increasing hospital admission rates for urological complications after transrectal ultrasound biopsy. J Urol 2010; 183: Rosario DJ, Lane JA, Metcalfe C, et al. Short term outcomes of prostate biopsy in men tested for cancer by prostate specific antigen: prospective evaluation within ProtecT study. BMJ 2012; 344:d Siddiqui M, Rais-Bahrami S, Turkbey B, et al. Comparison MR/ultrasound fusion-guided biopsy for the diagnosis of prostate cancer. JAMA 2015; 313: Turkbey B, Mani H, Aras O, et al. Prostate cancer: can multiparametric MR imaging help identify patients who are candidates for active surveillance? Radiology 2013; 268: 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: 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: D Amico AV. Risk-based management of prostate cancer. N Engl J Med 2011; 365: Wysock JS, Rosenkrantz AB, Huang WC, et al. A prospective, blinded comparison of the magnetic resonance (MR) imaging-ultrasound fusion and visual estimation in the performance of MR-targeted prostate biopsy: the PROFUS trial. Eur Urol 2014; 66: Delongchamps NB, Peyromaure M, Schull A, et al. Prebiopsy magnetic resonance imaging and prostate cancer detection: comparison of random and targeted biopsies. J Urol 2013; 189: Puech P, Rouviere O, Renard-Penna R, et al. Prostate cancer diagnosis: multiparametric MR-targeted biopsy with cognitive and transrectal US-MR fusion guidance versus systematic biopsy prospective multicenter study. Radiology 2013; 268: Tolonen TT, Kujala PM, Tammela TL, Tuominen VJ, Isola JJ, Visakorpi T. Overall and worst Gleason scores are equally good predictors of prostate cancer progression. BMC Urol 2011; 11: D Elia C, Cerruto M, Cioffi A, Novella G, Cavalleri S, Artibani W. Upgrading and upstaging in prostate cancer: from prostate biopsy to radical prostatectomy. Mol Clin Oncol 2014; 2: Berney DM, Algaba F, Camparo P, et al. The reasons behind variation in Gleason grading of prostatic biopsies: areas of agreement and misconception among 266 european pathologists. Histopathology 2014; 64: (Figures start on next page) AJR:208, March

5 A C A D Habibian et al. B D B E Fig year-old man with Gleason 6 (30% highest core involvement) prostate cancer who was monitored with active surveillance for 70 months. A C, Initial multiparametric MRI examination performed before active surveillance began. MR image (A) reveals focal moderately restricted diffusion (arrow, A) at left posterior mid to apex peripheral zone. T2-weighted image (B) shows corresponding area of hypointense signal (arrow, B), and dynamic contrast-enhanced image (C) shows focal early enhancement (arrow, C) without evidence of extraprostatic extension or seminal vesicle invasion. D, Follow-up multiparametric MRI examination performed 70 months after initial MRI examination because of rise in prostate-specific antigen value from 4 to 6 ng/ml over 1-month period. Follow-up DW images and contrast-enhanced MR images showed similar findings. This T2-weighted image shows that there is new capsular retraction and new irregularity of prostatic capsule at left posterior apex peripheral zone with abnormal rectoprostatic angle (arrow); these findings are consistent with extraprostatic extension. Transrectal ultrasound guided biopsy targeted to left apex peripheral zone revealed Gleason 8 adenocarcinoma at left lateral mid and left apex peripheral zone. C Fig year-old man with bilateral Gleason 6 prostate cancer and right Gleason 7 prostate cancer at transrectal ultrasound guided biopsy. A C, Initial multiparametric MRI examination performed before active surveillance began. Apparent diffusion coefficient (ADC) map (A) reveals patchy mild to moderate hypointense signal (arrow, A) at left posterolateral base to mid peripheral zone. T2-weighted image (B) shows same area exhibits hypointense signal (arrow, B). Dynamic contrastenhanced image (C) shows focal early enhancement (arrow, C). Patient was placed on active surveillance. D and E, Follow-up multiparametric MRI examination performed 10 months after initial MRI examination. ADC map (D) and T2-weighted image (E) reveal new severely hypointense lesion (arrows) at left lateral apex peripheral zone. (Fig. 2 continues on next page) 568 AJR:208, March 2017

6 MRI for Active Surveillance of Prostate Cancer F A G Fig. 2 (continued) 68-year-old man with bilateral Gleason 6 prostate cancer and right Gleason 7 prostate cancer at transrectal ultrasound guided biopsy. F and G, Lesion seen on follow-up MR images (D and E) was not present on T2-weighted image (F) and DW image (b = 2000 s/mm 2 ) (G) obtained as part of initial multiparametric MRI examination 10 months earlier. Area where lesion appeared on follow-up images is shown by star in F and arrowhead in G. C D E Fig year-old man with low-grade Gleason 6 (5% of core) prostate cancer at right base peripheral zone at initial transrectal ultrasound guided biopsy. A and B, Initial multiparametric MRI examination performed before active surveillance began. T2-weighted image (A) shows ill-defined mild hypointense signal at right posterolateral mid peripheral zone (arrow, A). Apparent diffusion coefficient (ADC) map (B) shows mild ill-defined restricted diffusion (arrow, B). No focal early enhancement was seen on initial dynamic contrast-enhanced MR images (not shown). Patient was placed on active surveillance. C E, Follow-up multiparametric MRI examination performed 2 years after initial MRI examination. T2-weighted image (C) reveals that area of hypointense signal at right posterolateral mid peripheral zone (arrow, C) is larger than it was on initial T2-weighted image (A). ADC map (D) shows increased restricted diffusion (arrow, D) compared with initial ADC map (B). Dynamic contrast-enhanced MR image (E) shows new focal early enhancement (arrow, E). In addition, new finding of capsule retraction is seen in this region, which suggests possibility of extracapsular extension. Patient was removed from active surveillance program and elected to undergo radiotherapy (Cyberknife, Accuray) without undergoing biopsy to confirm follow-up MRI findings. B AJR:208, March