Effect of Dutasteride Therapy on Doppler US Evaluation of Prostate: Preliminary Results 1

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1 Genitourinary Imaging Elizabeth P. Ives, MD Leonard G. Gomella, MD Ethan J. Halpern, MD Published online /radiol ; 237: Abbreviations: BPH benign prostatic hyperplasia PSA prostate-specific antigen 1 From the Departments of Urology (E.P.I., L.G.G.) and (E.J.H.), Kimmel Cancer Center, Thomas Jefferson University, 132 S 10th St, Philadelphia, PA Received September 7, 2004; revision requested November 10; revision received November 22; accepted December 17. Address correspondence to E.J.H. ( ethan.halpern@jefferson.edu). See Materials and Methods for pertinent disclosures. Effect of Dutasteride Therapy on Doppler US Evaluation of Prostate: Preliminary Results 1 PURPOSE: To prospectively determine the effect of short-term therapy with dutasteride on the suppression of Doppler ultrasonographic (US) signal in benign prostate tissue and thus on improvement in the depiction of prostate cancer with Doppler US guided core-needle biopsy. MATERIALS AND METHODS: After institutional review board approval and informed consent were obtained as part of this HIPAA-compliant study, 11 men (age range, years) were evaluated with gray-scale, color, and power Doppler US at baseline and weekly for up to 3 weeks while taking 0.5 mg of dutasteride per day. Flow intensity in the periurethral, transition, and peripheral zones was subjectively scored by using a four-point scale. The Wilcoxon matched-pairs signed-ranks test was used to compare pre- and posttherapy scores. After flow was reduced to diminished or none with at least a 1-score difference on the four-point scale, up to four targeted cores were obtained from areas of persistent flow within the peripheral zone, followed by laterally directed sextant biopsy. RESULTS: Doppler US flow suppression occurred in 11 of 11 patients after 1 week of dutasteride therapy (P.01). Further suppression was noted after 2 weeks in eight of 10 patients (P.04) and after 3 weeks in two of two patients. Biopsy was performed after 1 (n 1),2(n 8), or 3 (n 2) weeks of therapy. Flow suppression was greatest in the peripheral zones (mean decrease: 0.64 and 0.76 after weeks 1 and 2, respectively) and least in the periurethral zones (mean decrease: 0.30 after 1 week). Cancer was detected in eight (20%) of 40 targeted cores and in five (8%) of 66 sextant cores. Four patients had cancer at targeted biopsy, and three of these four patients had cancer at sextant biopsy. In the four men with cancer, targeted cores were 5.9 times more likely to be positive (P.027). Selective suppression of flow in benign tissue was observed in two of the four men with cancer. CONCLUSION: Short-term dutasteride therapy reduces Doppler US flow in the prostate and may improve depiction of hypervascular cancer. RSNA, 2005 Author contributions: Guarantors of integrity of entire study, E.P.I., E.J.H; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, E.P.I., E.J.H.; clinical studies, E.P.I., L.G.G., E.J.H.; statistical analysis, E.P.I., E.J.H.; and manuscript editing, E.P.I., L.G.G., E.J.H. RSNA, 2005 Ultrasonographic (US)-guided detection of prostate cancer is limited by the inability of conventional gray-scale and Doppler US to enable one to adequately distinguish malignant from benign prostate tissue. With gray-scale US, cancer of the prostate is classically described as hypoechoic in the peripheral zone but often appears isoechoic and can even appear hyperechoic (1,2). Because of the increased local angiogenesis associated with cancer of the prostate, improved cancer detection may be achieved on the basis of the color Doppler US blood flow characteristics of prostate cancer (3,4). However, both prostatitis and benign prostatic hyperplasia (BPH) are associated with increased Doppler US flow, and neither color nor power Doppler US results are specific for the diagnosis of prostate cancer (5 7). Dutasteride (Avodart; Glaxo-Smith-Kline, Phildadelphia, Pa), a type I/II 5- -reductase inhibitor, is approved for treatment of symptomatic BPH. Preliminary data for the selective type II 5- -reductase inhibitor finasteride suggest that prostatic blood flow may be reduced after short-term therapy with it for several weeks (8). This effect is probably related to a decrease in microvessel density within benign prostatic tissue (9). We reasoned that the reduction in Doppler US signal from the prostate is likely to be even more marked after 197

2 treatment with the more potent dual 5- reductase inhibitor dutasteride. Because 5- -reductase is down-regulated in prostate cancer (10), we hypothesized that short-term therapy with dutasteride might produce a selective reduction in Doppler US flow to benign tissue but have less effect on flow in prostate carcinoma. Thus, the purpose of our study was to prospectively determine the effect of short-term therapy with dutasteride on the suppression of Doppler US signal in benign prostate tissue and thus on improvement in the depiction of prostate cancer with Doppler US guided coreneedle biopsy of the prostate. MATERIALS AND METHODS GlaxoSmithKline supported this study by providing dutasteride and financial support for a study coordinator. The authors retained control of the data and the information submitted for publication. No authors are employees of or consultants for GlaxoSmithKline. One author (L.G.G.) is on the Reduction by Dutasteride in Prostate Cancer Events, or REDUCE, steering committee. Study Patients Patients referred by the Urology Department for transrectal US-guided biopsy of the prostate were offered enrollment into this study, which was compliant with the Health Insurance Portability and Accountability Act and approved by the institutional review board. Patients with a prior diagnosis of prostate cancer and those who were already taking a 5- reductase inhibitor or any herbal remedy for prostate health were excluded. All patients had been referred because of either a palpable nodule at digital rectal examination or an elevated serum prostatespecific antigen (PSA) level ( 4.0 ng/ml). Of the approximately 100 patients who were offered enrollment over a 6-month period (October 2003 to March 2004), 11 men provided informed consent to participate. The men ranged in age from 59 to 77 years and had a median age of 67 years. Three of the men had had a palpable nodule at digital rectal examination. PSA levels ranged from 0.9 to 9.1 ng/ml (mean, 5.5 ng/ml; median, 5.7 ng/ml). Ten patients identified themselves as white, and one identified himself as African-American. No patient was excluded on the basis of race or age. Four patients had previously undergone prostate biopsy that had yielded no findings of cancer. Medication Dutasteride capsules (0.5 mg) were given to patients in 2-week supplies. Patients were instructed to take one tablet orally each day starting immediately after the baseline US study. Medication was continued until the day of biopsy. Compliance with the prescribed medication was checked by asking the patient about the medication on each return visit and by checking the number of tablets remaining in the medication vial. Complete compliance was documented in all but one patient, who missed three doses. This man had a reduction in blood flow despite the missed doses. This patient was included in the analysis after the long half-life of dutasteride (up to 5 weeks in humans) was considered (11). US Procedure Each patient underwent a digital rectal examination followed by baseline transrectal prostate US prior to the administration of dutasteride. The same two physicians (E.P.I. and E.J.H.) together performed all of the US examinations and biopsies in this study. The physicians had 2 years (E.P.I.) and more than 10 years (E.J.H.) of experience with prostatic US. Patients were asked to abstain from ejaculation for 24 hours prior to each US evaluation. US was performed with the patients in the lithotomy position (12) with a Sequoia system (Siemens Medical Systems; Issaquah, Wash) and an EC10C5 end-fire probe. Doppler imaging was performed at the 9-MHz frequency setting. Transverse images of the prostate were obtained by sweeping from the base to the apex of the gland. Doppler gain settings were left at their default values for all studies. Default system settings were adjusted during the baseline examination to maximize the visualization of color flow within the prostate without producing color noise in stationary tissue. The same settings were used during follow-up examinations. Both color and power Doppler US flow within the prostate were subjectively scored during each study. Flow was scored by using a four-point scale in which a score of 0 indicated no flow; a score of 1, diminished flow; a score of 2, normal flow; and a score of 3, increased flow. Each patient started taking 0.5 mg of dutasteride per day immediately after the baseline US study and returned weekly for repeat US and Doppler evaluation of the prostate. On each return visit, Doppler flow was evaluated with transrectal US and subjectively scored. Each patient underwent prostate biopsy only after flow within the prostate was suppressed to none or diminished with at least a 1-score reduction in flow. Immediately before each follow-up US study, a videotape of the previous week s study was reviewed by the examining physicians (E.P.I. and E.J.H.). Each US examination included gray-scale, color, and power Doppler US performed in a transverse orientation from the base to the apex. Color and power Doppler US flow were scored in 12 regions that is, in four areas (the transition zone, the periurethral area, and the right and left peripheral zones) in the base, middle, and apex of each gland. Diminished or increased flow was scored with respect to the expected flow pattern in a normal prostate in a man who had not undergone dutasteride therapy. All scoring was performed before any biopsy or administration of lidocaine anesthetic. A consensus reading of all Doppler US studies was performed by the two examining physicians, and a Doppler US flow score was chosen for color and power Doppler US in each of the 12 regions. The consensus reading was used for statistical analysis. Biopsy Procedure Prostate biopsy was performed once overall blood flow was deemed to have reduced to a score of 0 or 1 with a decrease of at least one score in at least one region from the flow score assigned at the baseline study. A minority of patients (three or four) who were taking aspirin before the procedure were included in the study. Once a decrease in blood flow of at least one score was observed, each of these patients was advised to stop taking aspirin and to use a saline laxative enema (Fleet, Lynchburg, Va) before the next US examination in anticipation of biopsy. Biopsy in one patient who stopped taking aspirin was deferred for an additional week until the Doppler US flow reached a score of 0 or 1, while the remaining patients required only a single week off aspirin before biopsy could be performed. Patients who were not taking aspirin and whose blood flow demonstrated a onescore decrease from the score given at the baseline study were advised to use an enema before subsequent US. In one patient in whom overall blood flow was markedly reduced after 1 week of dutasteride, an enema was administered and biopsy was performed at the time of the first follow-up US study. The same two physicians (E.P.I., with 2 years of experience, and E.J.H., with 198 October 2005 Ives et al

3 Figure 1. Transverse US images of prostate in 76-year-old white man with an elevated PSA level and an adenocarcinoma with a Gleason score of 7 that was found at directed biopsy of the base and midgland. Arrows mark the sites of targeted biopsy cores. (a, b) Color Doppler US images through the midgland obtained (a) at baseline and (b) after 3 weeks of dutasteride therapy. (c, d) Power Doppler US images through the midgland obtained (c) at baseline and (d) after 3 weeks of dutasteride therapy. The baseline images show increased Doppler US flow throughout the gland. The posttreatment images show reduced overall Doppler US flow with persistent flow in the peripheral areas that contained malignancy. more than 10 years of experience) performed or assisted at all biopsies. All patients received antibiotics before biopsy. Five hundred milligrams of ciprofloxacin (Cipro; Ivax Pharmaceuticals, Miami, Fla) was administered orally in the procedure room. One patient who required endocarditis prophylaxis received intravenous ampicillin (American Pharmaceutical Partners, Schaumburg, Ill) and gentamicin (Abbott Laboratories, North Chicago, Ill) before biopsy. Oral antibiotics were continued for 48 hours after biopsy. Ten milliliters of lidocaine 2% (Abbott Laboratories) without epinephrine was administered transrectally before biopsy (5 ml of lidocaine was administered along the neurovascular bundle on each side of the prostate). Biopsy was performed after gray-scale and color and power Doppler US evaluation. Targeted biopsy was directed to areas that had the most remaining blood flow in the peripheral zone on the basis of either color or power Doppler US data. Targeted biopsies were followed by a laterally directed systematic sextant biopsy (13). Sextant cores were obtained from the peripheral zone at the base, middle, and apex of the gland on each side without regard to Doppler US findings. However, when an area of gray-scale abnormality was present within a sextant of the prostate, the corresponding sextant biopsy was adjusted to include the abnormality. All biopsy cores were obtained with an 18-gauge core biopsy gun (Pro-Mag Biopsy Needle; Medical Device Technologies, Gainesville, Fla). Specimens obtained with Doppler US guidance were labeled as directed, and the location of the core within the prostate was noted; sextant specimens were simply labeled according to location (right or left and base, middle, or apex). Pathology Reports Pathology reports for each specimen were reviewed by a staff pathologist with at least 5 years of experience, and each specimen was recorded as benign or malignant. Gleason scores for malignant specimens were recorded. The presence of prostatitis was recorded. Targeted and sextant cores were then separately evaluated for the rate of positive biopsy results. Statistical Analysis Reduction in prostatic blood flow was documented by changes in the subjective scores assigned at Doppler US evaluation. The Wilcoxon matched-pairs signed-ranks test was used to compare each of the 12 regional posttherapy subjective scores to earlier scores given to the same location at the baseline examination or during earlier weeks of therapy. A significant result with the Wilcoxon matched pairs signedranks test demonstrated that the observed change in blood flow from week to week was not related to random chance. To compare the rate of positive biopsy cores among directed and systematic biopsies, conditional logistic regression was performed (Stata 8.0; Stata; College Station, Tex). This technique compensates for the lack of independence of multiple biopsy samples within each patient. As implemented in Stata 8.0, the clogit regression option allows for variation in the number of cases and controls in each matched group. A P value of less than.05 was considered to indicate a statistically significant difference. RESULTS Biopsies Data from all men who enrolled in the study are included in the results. Four patients were given a diagnosis of prostate cancer. Biopsy was performed after 1 (n 1),2(n 8), or 3 weeks (n 2) of therapy. A total of 106 biopsy cores were obtained: Sixty-six cores were laterally directed sextant cores obtained by using gray-scale US, and 40 cores were obtained at targeted biopsy directed to sites with residual Doppler US signal after dustasteride therapy. Between two and four (mean, 3.63) targeted biopsy cores were obtained from one to four regions (mean, 2.45). Flow Suppression On the basis of the consensus readings of the regional Doppler US signal by the two physicians, suppression of Doppler flow by at least one score in at least one region was noted in 11 of 11 patients after 1 week of dutasteride therapy (P.01) with both color and power Doppler US. When compared with flow after 1 week of dutasteride therapy, flow was further suppressed after 2 weeks of therapy in eight of 10 patients (P.04). Two patients returned for repeat US and biopsy after 3 weeks of dutasteride treatment because they had flow that was re- Volume 237 Number 1 Effect of Dutasteride on Doppler US of Prostate 199

4 duced but was still within the subjective normal or increased flow ranges. After 3 weeks of treatment, there was reduction in the subjective flow score to below the normal range in both of these patients. Suppression of Doppler US signal after therapy was most obvious in the peripheral zone (mean decrease: 0.64 after 1 week and 0.76 after 2 weeks) and least obvious in the periurethral zone after 1 week of treatment (mean decrease: 0.30). However, after 2 weeks the reduction of flow in the periurethral zone was comparable to that in the peripheral zone (mean decrease: 0.67). Biopsy Results Cancer. Prostate cancer was detected in four patients. Pathologic evaluation revealed that the area(s) of malignancy had a Gleason score of 6 in two patients, Gleason scores of 6 and 7 in one patient, and a Gleason score of 8 in one patient. Targeted biopsy revealed cancer in all four of these patients. Sextant biopsy also revealed the tumor in three of the four patients. In one patient, none of the sextant cores were positive, while one of three targeted biopsy cores showed a tumor with a Gleason score of 6. Three of the four patients with biopsy-proved cancer had at least one directed biopsy core that revealed cancer in a region that was not revealed with sextant biopsy alone. Gleason scores were the same at directed and sextant biopsy in two patients. The Gleason score was 6 at sextant and 7 at directed biopsy in the other patient. Cancer was detected in eight (20%) of 40 targeted biopsy cores and in five (8%) of 66 sextant cores. In the four patients with cancer, conditional logistic regression analysis revealed that targeted cores were 5.9 times more likely to be positive for cancer (P.027). Prostatitis. Prostatitis (either acute or chronic) was diagnosed at biopsy in four patients. None of these patients were also diagnosed with cancer. The rate of prostatitis detection was similar between sextant (seven [11%] of 66 cores) and directed (four [10%] of 40 cores) biopsy. Selective suppression of flow in benign prostatic tissue was observed in two of the four patients with cancer. The sites of cancer were more obvious in these patients after dutasteride therapy (Figs 1, 2). Both of these patients had multiple positive cores at directed biopsy. Complications One patient reported experiencing headaches in the first several days of dutasteride Figure 2. Transverse US images of prostate in 67-year-old white man with an elevated PSA level and an adenocarcinoma with a Gleason score of 8 that was found at both directed and sextant biopsy only along the left side of the prostate, from the base to the apex. Arrows mark the sites of positive targeted biopsy cores in the midgland. (a, b) Color Doppler US images through the midgland obtained (a) at baseline and (b) after 2 weeks of dutasteride therapy. (c, d) Power Doppler US images through the midgland obtained (c) at baseline and (d) after 2 weeks of dutasteride therapy. The baseline images show Doppler US flow in the transition zone, as well as on both sides of the peripheral zone. The posttreatment images show reduced overall Doppler US flow, with persistent flow only in the left peripheral zone, which contained tumor. treatment; these headaches resolved spontaneously. No other adverse events were reported. There were no other complications resulting from the medication, US examinations, or biopsy procedures. DISCUSSION Our study results demonstrate suppression of Doppler US flow in both the peripheral and transition zones of the prostate after short-term oral therapy with dutasteride. In two patients, the suppression of Doppler US flow afforded better depiction of hypervascular areas of malignancy. Results of previous investigations have indicated that Doppler US, even when performed by an experienced sonographer, is only minimally better than conventional gray-scale US for distinguishing benign from malignant tissue (14). The poor discrimination of benign from malignant tissue is due in part to the color Doppler US signal arising from areas of benign disease such as BPH and prostatitis (15). Although most visible BPH nodules develop in the transition zone or in periurethral tissue, BPH has been identified at pathologic evaluation of the peripheral zone (15 20). In our small series, shortterm therapy with dutasteride appeared to reduce visible Doppler US flow in all areas of the prostate, including the peripheral zone. This reduction is likely due to rapid short-term alterations in blood flow that are similar to the decreased microvessel densities previously reported to occur in patients treated with finasteride (9). Prostatitis is often considered an important cause of false-positive results at color Doppler US imaging of the prostate. In the present study, a negligible difference was observed in the detection rate of prostatitis between directed and sextant biopsies. This result suggests that the Doppler US signal associated with prostatitis, along with the Doppler US signal associated with other benign prostate tissues, is suppressed by dutasteride. The optimal duration for short-term therapy with dutasteride before biopsy is 200 October 2005 Ives et al

5 difficult to determine. Patients start with different levels of Doppler US flow, and the time course of the response may differ from one patient to the next. In this small series, noticeable flow reduction occurred in the 1st week, but discriminating changes could be seen in two patients for up to 3 weeks. Longer-term effects of dutasteride therapy on flow patterns in benign prostatic tissue are not known; nor is it known whether longer treatment can suppress cancer vascularity and affect Gleason score (21). This study was a preliminary investigation and was limited by its small size. The two observers were blinded neither to the fact that patients were taking dutasteride nor to the results of examinations performed in previous weeks. Intraobserver and interobserver variability were not measured. Finally, the lack of wholemount pathologic correlation in patients with negative biopsy results leaves open the possibility that some cancers were not detected. Although it is possible that cancer was missed in some patients, the overall cancer detection rate of four is reasonable in a population of 11 patients, all of whom had PSA levels of less than 10 ng/ml and four of whom had previous negative biopsy results. Most important, our findings suggest that short-term oral therapy with dutasteride may effect a selective reduction in blood flow to benign tissue and improve targeting at color Doppler US guided biopsy. Two of the four patients with cancer in this study had persistent strong Doppler US signal in areas of malignancy even though there was a clear reduction in Doppler US signal throughout the gland after therapy with dutasteride. A larger blinded controlled follow-up trial is needed to determine whether shortterm therapy with dutasteride may reduce the false-positive rate of Doppler US evaluation and improve the utility of Doppler US in the identification of prostate cancer with fewer biopsy cores. In conclusion, short-term dutasteride therapy reduces Doppler US flow in the prostate, including in areas of prostatitis, and may improve the depiction of hypervascular cancer. Biopsy targeted toward areas of persistent flow after dutasteride therapy improved detection of prostate cancer compared with systematic sextant biopsy. Optimal prebiopsy treatment with dutasteride appears to be 2 3 weeks. References 1. Rifkin MD, Dahnert W, Kurtz AB. State of the art: endorectal sonography of the prostate gland. AJR Am J Roentgenol 1990;154: Dahnert WF, Hamper UM, Eggleston JC, Walsh PC, Sanders RC. Prostatic evaluation by transverse sonography with histopathologic correlation: echogenic appearance of early carcinoma. 1986;158: Rifkin MD, Sudakoff GS, Alexander AA. Prostate: techniques, results and potential applications of color Doppler US scanning. 1993;186: Sudakoff GS, Smith R, Vogelzang NJ, Steinberg G, Brendler CB. 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Finasteride effect on prostatic hyperplasia and prostate cancer: a comparative clinicopathologic study of radical prostatectomies. J Urol Pathol 1997;6:1 14. Volume 237 Number 1 Effect of Dutasteride on Doppler US of Prostate 201