Diffusion-Weighted Imaging to Evaluate for Changes From Androgen Deprivation Therapy in Prostate Cancer

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1 Genitourinary Imaging Original Research Kim et al. DWI of Prostate Cancer Patients Treated With ADT Genitourinary Imaging Original Research Ah Yeong Kim 1 Chan Kyo Kim Sung Yoon Park Byung Kwan Park Kim AY, Kim CK, Park SY, Park BK Keywords: androgen deprivation, biomarker, diffusionweighted imaging, MRI, prostate cancer DOI: /AJR Received November 18, 2013; accepted after revision March 30, All authors: Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul , Republic of Korea. Address correspondence to C. K. Kim (chankyokim@skku.edu). WEB This is a web exclusive article. AJR 2014; 203:W645 W X/14/2036 W645 American Roentgen Ray Society Diffusion-Weighted Imaging to Evaluate for Changes From Androgen Deprivation Therapy in Prostate Cancer OBJECTIVE. The objective of our study was to investigate the usefulness of apparent diffusion coefficient (ADC) values in evaluating for therapeutic changes from androgen deprivation therapy (ADT) in prostate cancer patients. MATERIALS AND METHODS. Forty-eight patients with prostate cancer treated with ADT were enrolled in this retrospective study. Diffusion-weighted imaging (DWI) at 3 T was performed before and after ADT. Before and after treatment, ADC values were measured in the tumors and in the benign tissues of the prostate, and serum prostate-specific antigen (PSA) levels and prostate volumes were also assessed. Statistical analysis was performed using a paired Student t test, Wilcoxon signed rank test, and Spearman rank correlation. RESULTS. In 48 patients, 55 tumors were identified. After treatment, the mean ADC value of the tumors ( mm 2 /s) was significantly increased as compared with the pretreatment value ( mm 2 /s) (p < 0.001), whereas the ADC values of the benign tissues after treatment were significantly decreased compared with the pretreatment values (p < 0.001). The mean prostate volume and mean PSA level were significantly reduced from 42.8 cm 3 and ng/ml before treatment to 21.4 cm 3 and 9.51 ng/ml, respectively, after treatment (p < 0.001). Changes in tumor ADC values showed a weak negative correlation with changes in PSA levels after treatment (correlation coefficient, ρ = 0.320; p = 0.028). CONCLUSION. DWI may have potential as a noninvasive tool for monitoring changes in response to ADT in prostate cancer patients. A ndrogen deprivation therapy (ADT) is commonly used to treat patients with metastatic prostate cancer [1]. In locally advanced prostate cancer, it is used as adjuvant therapy with radiotherapy and when the patient is not a candidate for radical local treatment [1 3]. ADT is also used to treat patients with increasing serum prostate-specific antigen (PSA) levels after local treatment [1, 3]. Although ADT may slow disease progression, it is not considered a curative treatment. In a recent study, approximately 37% of patients with advanced local or metastatic prostate cancer treated with ADT had disease progression after a median follow-up of 51 months [4]. Currently, there are many unresolved issues with ADT, including the optimal times for the initiation and termination of ADT. Therefore, follow-up after ADT should be tailored to the individual patient according to each patient s symptoms, prognostic factors, and treatment received. For individualized treatment, a noninvasive tool of assessing the effectiveness of treatment and accurately measuring the presence and local extent of residual cancer is necessary. After patients with prostate cancer receive ADT, monitoring or assessing the therapeutic effects of ADT is performed using serum PSA values, testosterone levels, and a screening test for metabolic syndrome [1]. The serum PSA value has probably been the most studied biomarker [5]. The identification of PSA parameters, such as PSA velocity, PSA doubling time, and nadir PSA which are predictive of progression to hormone-refractory prostate cancer may be helpful for further planning of the treatment strategy [6]. However, disease progression occurs after ADT in approximately 20% of patients with PSA levels of less than 4.0 ng/ml [7], and it is unclear whether PSA value is a valid surrogate for survival in hormonally treated prostate cancer [8]. Furthermore, no pattern of PSA kinetics after ADT can conclusively distinguish between local and distant tumor recurrence in advanced prostate cancer. On the AJR:203, December 2014 W645

2 Kim et al. contrary, functional MR techniques such as diffusion-weighted imaging (DWI) may detect and localize prostate cancer before ADT and then may supply qualitative or quantitative information for measuring therapeutic response in prostate cancer patients during and after ADT. DWI exploits the brownian movement of water molecules within tissues as a biomarker that correlates with cellularity [9]. Conceptually, effective treatment of a tumor leads to disruption of cellular integrity and to subsequent loss of overall cellular density, resulting in an increase of diffusion values detectable by DWI. Apparent diffusion coefficient (ADC) values from DWI parametric maps provide quantitative data on tissue diffusivity, which reflects cell death and necrosis in response to treatment [10]. Until recently, many studies have reported on the usefulness of DWI in the practice of clinical oncology, such as for tumor identification and treatment response monitoring [11]. In prostate cancer, several studies have reported a possibility of DWI as an imaging biomarker in assessing or predicting therapeutic response after local treatment [12 14]. However, to our knowledge, few investigations have addressed the role of DWI in monitoring or assessing therapeutic response to ADT in prostate cancers [15, 16]. Therefore, the purpose of this study was to retrospectively investigate the usefulness of ADC values in evaluating changes in response to ADT in prostate cancer patients. Materials and Methods Patients This retrospective study was approved by our institutional review board, and written informed consent was waived. Between April 2008 and December 2012, 48 patients (mean age, 67.2 years; range, years) with biopsy-proven prostate cancer received ADT as palliative or neoadjuvant treatment before radiotherapy. All 48 patients underwent MRI at 3 T using a phased-array coil before and after ADT in our institution. None of the patients received any other treatments before ADT. MRI was performed 2 months after the initiation of ADT or immediately before the initiation of any other treatments such as radiotherapy, chemotherapy, or surgery in patients scheduled to undergo combined treatments. The mean followup period was 4 months (range, 1 15 months). During the follow-up period, serum PSA values were checked every 1 month after ADT was started according to the clinical protocols of our institution. The characteristics of the selected patients are summarized in Table 1. TABLE 1: Characteristics of Study Group Before ADT: 48 Patients With 55 Prostate Cancer Tumors Characteristic ADT was administered according to the standard regimen of our institution as follows: bicalutamide (n = 4 patients); combination of bicalutamide and goserelin (n = 5); combination of bicalutamide and triptorelin (n = 12); combination of bicalutamide and leuprorelin (n = 9); combination of bicalutamide, goserelin, and triptorelin (n = 10); combination of bicalutamide, goserelin, and leuprorelin (n = 6); and combination of bicalutamide, goserelin, triptorelin, and leuprorelin (n = 2). ADT was given as a neoadjuvant treatment before radiotherapy in 37 patients and as palliative management in the remaining 11 patients. The time interval between the initiation of neoadjuvant treatment and radiotherapy ranged from 1 to 10 months (mean, 4 months). All patients underwent a transrectal ultrasound (TRUS)-guided biopsy within a median of 33 days (range, 1 56 days) before ADT. TRUS-guided biopsies were performed before the initial MRI examination (range, 8 51 days; mean, 27 days) in 45 patients, and targeted biopsies were performed after the MRI examination in the remaining three patients (1, 12, and 18 days after MRI). Value Patient age (y) Mean 67.2 Range Tumor size at MRI (cm) Mean 2.3 Range Gleason score Median 8 Range 6 9 No. of patients with Gleason score of 6 2 No. of patients with Gleason score of 7 19 No. of patients with Gleason score of 8 16 No. of patients with Gleason score of 9 11 T stage at MRI (no. of patients) T2b 1 T3a 16 T3b 30 T4 1 Lymph node metastasis (no. of patients) 28 Distant metastasis (no. of patients) 13 Note ADT = androgen deprivation therapy. MRI Protocol All MRI examinations were performed using a 3-T MR system (Intera Achieva, Philips Healthcare) equipped with a phased-array coil. An intramuscular injection of 20 mg of butyl scopolamine (Buscopan, Boehringer Ingelheim) was administered to suppress bowel peristalsis, and the urinary bladder was emptied before scanning began. T2-weighted turbo spin-echo images were obtained in three orthogonal planes (transverse, sagittal, and coronal) with the following parameters: TR range/te range, /80 90; slice thickness, 3 mm; interslice gap, mm; matrix, or ; FOV, mm; and sensitivity-encoding (SENSE) factor, 2. DWI with the single-shot echo-planar imaging technique was performed in a transverse plane. The following imaging parameters were used: TR range/te range, /63 75; slice thickness, 3 mm; interslice gap, 1 mm; matrix, ; FOV, 200 mm; SENSE factor, 2; and b values, 0 and 1000 s/mm 2. ADC maps were automatically measured by the imager software with the use of the two b values. Image Analysis Two genitourinary radiologists with 7 and 9 years of experience in interpreting prostate MR examinations, respectively, reviewed retrospectively all MR images in consensus. They were blinded to W646 AJR:203, December 2014

3 DWI of Prostate Cancer Patients Treated With ADT all patient information except whether the patient had pathologically proven prostate cancer. However, if the two readers disagreed about the exact tumor localization on the MR images, consensus was reached using information from digital rectal examination or pathologic results of biopsies. On MR images, a tumor was considered to be present if a focal low-signal-intensity area seen in the prostate on ADC maps revealed high signal intensity on index DWI [17] with or without the use of T2-weighted images. Before and after treatment, the ADC values of tumors and benign prostatic tissues including the peripheral zone (PZ) and transition zone (TZ) were measured using placement of ROIs by consensus of the two readers. ROIs were carefully drawn to exclude the neurovascular bundles and the urethra in an attempt to decrease errors in ADC measurements. Before treatment, an ROI of the tumor in the PZ or TZ was drawn on ADC maps to include as much of the tumor as possible. The tumor ADC value was calculated on the ADC map that showed the greatest transverse diameter of the tumor, and the ADC values were measured twice in the same site during the same review session and by the same readers, and the average was recorded. Tumors with a transverse largest diameter of 0.5 cm or greater on the ADC maps were included, and high-resolution transverse T2-weighted images corresponding to the ADC maps were used to help the detailed anatomic visualization of the prostate. In the PZ and TZ of benign tissue, the ADC values were measured at the contralateral side of the tumor, and the size of each ROI was approximately 10 mm 2. In two different sites of benign tissue, ADC values on ADC maps were calculated, and the average was recorded. In cases of advanced prostate cancer in which tumor had replaced the entire prostate, ADC measurements of benign tissue were skipped. After treatment, if a tumor was not visible or was ill defined in the prostate, the ADC measurements on ADC maps were performed at the same area as that initially used before treatment. The ADC measurements were assessed twice at the same site, and the average was recorded. For benign tissues, the ADC measurements on ADC maps were performed at the same area that was initially used before treatment, and the average was recorded. The size of each ROI was approximately 10 mm 2. In cases of hormone-refractory prostate cancer that was progressing despite optimal treatment, we put the ROIs in the tumors and measured the ADC values in the same manner as we did on the initial MRI analysis. The mean size of the ROIs for the tumors was mm 2 (range, mm 2 ) before treatment and mm 2 (range, mm 2 ) after treatment. TABLE 2: Apparent Diffusion Coefficient (ADC) Values of 55 Tumors in 48 Patients and of Benign Prostate Tissues in 43 Patients Before and After Androgen Deprivation Therapy (ADT) Prostate Before ADT Statistical Analysis The linear mixed-effects model was used to compare the ADC values before and after treatment between tumors and benign PZ, between tumors and benign TZ, and between tumors and benign tissue. The Wilcoxon signed rank test was used to compare the mean PSA levels and mean prostate volumes before and after treatment. The changes in pre- and posttreatment tumor ADC values were correlated with the changes in preand posttreatment serum PSA levels using the Spearman rank correlation. A significant difference was considered when p value < Statistical analyses were performed using statistics software (SPSS, version 20.0, IBM Software). Results In 48 patients, 55 cancers (PZ, n = 14 tumors; both PZ and central zone, n = 4; both PZ and TZ, n = 21; and all three zones of the prostate gland, n = 16) were found. On the ADC maps obtained before ADT, the mean tumor size was 2.3 cm (range, cm). ADC measurements were not available in benign PZ (n = 2 patients), benign TZ (n = 4), and both benign PZ and TZ (n = 3). Table 2 presents the ADC values of the 55 tumors in 48 patients and of the benign tissues in 43 patients before and after ADT. After ADT, the mean ADC value of the tumors ( mm 2 /s) was significantly elevated compared with the pretreatment value ( mm 2 /s) (p < 0.001) (Figs. 1 and 2), whereas the mean ADC values ADC a ( 10 3 mm 2 /s) After ADT Tumor 0.78 ± 0.13 ( ) 1.06 ± 0.21 ( ) < Benign tissues c 1.52 ± 0.21 ( ) 1.38 ± 0.19 ( ) < Benign PZ 1.61 ± 0.20 ( ) 1.47 ± 0.21 ( ) < Benign TZ 1.42 ± 0.15 ( ) 1.30 ± 0.14 ( ) < Note PZ = peripheral zone, TZ = transition zone. a Data are presented as mean ± SD (range). b Comparisons between values obtained before ADT and after ADT. c Mean value of benign PZ and benign TZ. TABLE 3: Changes in Prostate-Specific Antigen (PSA) Values and Prostate Volumes Before and After Androgen Deprivation Therapy (ADT) Time PSA (ng/ml) Prostate Volume (cm 3 ) Before ADT ± ( ) 42.8 ± 26.1 ( ) After ADT 9.51 ± ( ) 21.4 ± 14.2 ( ) Note Data are presented as mean ± SD (range). of the benign tissues (PZ = 1.47 and TZ = mm 2 /s) after ADT were significantly decreased compared with the pretreatment values (PZ = 1.61 and TZ = mm 2 /s) (p < 0.001). Fifty of 55 tumors showed an increase in the mean ADC values after treatment, whereas the five remaining tumors (five patients) had a decrease in the mean ADC values. Of these five patients, three had a recurrence during follow-up after ADT: bone metastasis (n = 1 patient), bone and hepatic metastases (n = 1), and lymph node metastasis (n = 1). The remaining two patients had no recurrence. Before ADT, the mean ADC value of tumors was significantly lower than the corresponding values of the benign tissues (p < 0.001). After ADT, a significant difference between the mean ADC values of tumors and of benign tissues was also noted (p < 0.001) (Table 2). The mean PSA level and mean prostate volume before ADT were significantly decreased after ADT (p < 0.001) (Table 3). The mean volume of the prostate after ADT was reduced in 50.0%. The change in tumor ADC values before and after ADT had a weak negative relationship with the change in PSA levels (correlation coefficient, ρ = 0.320; p = 0.028) (Fig. 3). No correlations between baseline tumor ADC values and changes in PSA levels after ADT were found (correlation coefficient, ρ = 0.197; p = 0.185). p b AJR:203, December 2014 W647

4 Kim et al. A B Fig year-old man treated with androgen deprivation therapy for T3a prostate cancer. A, Apparent diffusion coefficient (ADC) map obtained before treatment shows right transition zone tumor (red line) with ADC value of mm 2 /s. ADC value of benign left peripheral zone (blue line) is mm 2 /s. B, ADC map obtained after treatment reveals increased tumor (red line) ADC value ( mm 2 /s) in site that corresponds to site shown in A. However, ADC value of benign left peripheral zone (blue line) has decreased from mm 2 /s, as shown in A, to mm 2 /s after treatment. After treatment, prostate-specific antigen level had significantly decreased from 94.1 to 0.57 ng/ml. During the follow-up period, 11 of 48 (22.9%) patients developed recurrent or metastatic prostate cancer with metastasis to bone, liver, lung, or the lymph nodes or hormone-refractory prostate cancer; thus, disease in these patients was managed with additional treatment modalities including palliative chemotherapy or radiotherapy. Discussion DWI as a functional imaging technique can be used to calculate the mobility of water molecules within tissue and to depict tumor size and morphology [11]. Changes in ADC values are negatively related to changes in cellularity [10, 11]: Rises in ADC values reflect a rise in water mobility through a decrease in cellular size or number, and decreases in ADC values reflect a decrease in total free extracellular water by an increase in total cellular size or number, as shown with fibrosis, edema, or tumor progression. Our study showed that ADC values before ADT were significantly lower in prostate tumors than in benign prostate tissues, as shown in prior studies [18 20]. In prostate tumors, lower ADC values may reflect the restriction of water mobility due to the dense high cellularity of prostate cancer. To date, a few studies have shown changes in ADC values of prostate cancer after radiotherapy with or without ADT as compared with pretreatment values [12, 14, 21]. However, to our knowledge, few studies have reported on the role of DWI in evaluating therapeutic response before and after ADT alone [15, 16]. In our study, ADC values of prostate tumors increased significantly after ADT, which is consistent with the results of a recent study [16] that investigated ADC changes of Fig. 2 Graph of apparent diffusion coefficient (ADC) values in 55 prostate tumors before and after androgen deprivation therapy (ADT) shows statistically significant increase in ADC values in 50 of 55 tumors. ADC ( 10 3 mm 2 /s) Before ADT prostate cancer in only three patients. These changes in ADC maps might be explained by the correlation with the net decrease of glandular ducts (i.e., net decrease of cellular size or number in tumors) within the atrophic prostate cancer tissue as the result of apoptosis after ADT [22 24]. These histopathologic changes might alter the degree of water molecule diffusion within treated prostate tumors After ADT W648 AJR:203, December 2014

5 DWI of Prostate Cancer Patients Treated With ADT and might result in an increase in ADC values after ADT. However, a recent study showed a conflicting result of no significant change in ADC values in prostate tumors after ADT [15]. This discrepancy might result from different locations of ROIs in the tumors after treatment because prostate volume and tumor size are significantly decreased after treatment. In our study, in cases of no visible or illdefined residual tumor within the prostate, the ROIs were drawn in the same area as initially used before treatment. However, the authors of that previous study [15] did not mention the placement of tumor ROIs after ADT in detail. Other causes for the discrepant results between our study and the previous study [15] might include different DWI parameters or different type, duration, and dose of ADT. As compared with a prior study [15] that showed a significant decrease in ADC values in normal-appearing PZ after ADT, our results showed a significant decrease in ADC values for the PZ and TZ of benign prostate tissues after ADT. Several previous studies have reported the histologic findings in surgical specimens obtained from radical prostatectomy followed by neoadjuvant ADT revealed significant involutional changes in benign prostate tissue as well as residual prostate cancer [25]. These changes in benign prostate tissue after ADT include glandular atrophy, fibrosis, basal cell hyperplasia, and stromal hypercellularity, all of which reduce overall glandular stromal tissue and gland volume [24] and may cause a decrease in ADC values of benign prostate tissue after ADT [15]. Moreover, a decrease in ADC values of benign prostate tissues after ADT might result from a decrease in fluid in the extracellular space [9]. A recent study showed that baseline tumor ADC value as an indicator for predicting therapeutic response in prostate cancer had a negative correlation to an eventual change in PSA values after ADT [15]. Giles et al. [26] reported that baseline tumor ADC values were predictive of progression in patients with prostate cancer under active surveillance. Park et al. [13] reported that baseline tumor ADC values might be a predictive marker for biochemical failure after radical prostatectomy. In our study, baseline tumor ADC values before ADT did not show significant correlation to changes in PSA levels, but changes in tumor ADC values before and after ADT revealed a weak negative relationship with changes in PSA levels: The greater the increase in ADC values due to tumor cell Fig. 3 Graph shows relationship between change of apparent diffusion coefficient (ADC) values in prostate tumors and change of prostatespecific antigen (PSA) levels after androgen deprivation therapy. Note weak negative correlation between changes in tumor ADC values and changes in PSA levels (correlation coefficient, ρ = 0.320; p = 0.028). Line = linear regression. PSA Change (ng/ml) lysis or apoptosis, the greater the decrease in PSA levels. These results of our study suggest that tumor ADC values might be a useful marker for predicting therapeutic response to ADT, but further validation is needed. In our study, the mean ADC value of the tumors after ADT was still significantly lower than the mean ADC values of the benign tissues before treatment, which is consistent with the results of a previous study [15]. These findings might be explained histopathologically by the fact that all prostates contain residual cancer after ADT, although it may be extremely focal in up to 25% of cases [24]. ADT may reduce the volume of tumors but will not necessarily cause the downstaging of prostate cancer. Glandular volume reduction after ADT has a direct treatment benefit because the radiotherapy target volume is smaller, thus reducing irradiation of the bladder and rectum [27]. Changes in prostate tumor volume during neoadjuvant ADT may be predictive of prostate cancer recurrence in men treated with radiotherapy [28]. Kojima et al. [29] reported that the maximum effect of ADT occurs at 3 4 months. A 10 52% reduction in whole prostate volume has been widely reported [30 32]. In agreement with those findings, our findings show a 50% reduction in mean volume of the prostate after a mean 4 months of ADT. Our study has several limitations. First, no correlations between MR images and histopathologic findings were investigated because we could not acquire surgical specimens. Preclinical animal studies may reveal a detailed correlation between MR images ADC Change (10 3 mm 2 /s) and histopathologic findings during or after ADT. Second, we did not evaluate for an association of baseline tumor ADC values and clinical outcomes, such as progression-free survival or overall survival rate, because of the short follow-up period after ADT. Third, our study had a retrospective design and a relatively small study population, which might have led to selection or information bias. A larger future study may strengthen the results with respect to the usefulness of DWI in evaluating or monitoring therapeutic response to ADT in prostate cancer patients. Finally, our study had the possible limitation of ADC measurement errors in tumors and benign prostate tissues due to volume shrinkage of normal prostate tissue and of tumors during or after ADT. In conclusion, our preliminary results show that ADC values in prostate cancer tumors significantly increase after ADT; thus, DWI may be useful as a noninvasive tool for monitoring therapeutic changes in response to ADT in patients with prostate cancer. 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