european urology 53 (2008) 112 117 available at www.sciencedirect.com journal homepage: www.europeanurology.com Prostate Cancer Dutasteride Prior to Contrast-Enhanced Colour Doppler Ultrasound Prostate Biopsy Increases Prostate Cancer Detection Michael Mitterberger a, *, Germar Pinggera a, Wolfgang Horninger a, Hannes Strasser a, Ethan Halpern b, Leo Pallwein a, Johann Gradl a, Georg Bartsch a, Ferdinand Frauscher a a Departments of Urology and Radiology II, Medical University Innsbruck, Innsbruck, Austria b Division of Diagnostic Ultrasound, Thomas Jefferson University, Philadelphia, PA, USA Article info Article history: Accepted February 9, 2007 Published online ahead of print on February 20, 2007 Keywords: Dutasteride Contrast-enhanced colour Doppler ultrasound Prostate biopsy Abstract Objectives: This study assessed the effect of premedication with dutasteride, a dual 5a-reductase inhibitor, on prostatic blood flow prior to prostate biopsy and its impact on prostate cancer detection. Methods: Thirty-six patients, aged 52 74 yr, with elevated prostatespecific antigen (PSA) levels (1.25 ng/ml and free-to-total ratio of <18%) were treated with dutasteride 14 d prior to prostate biopsy. Contrast-enhanced colour Doppler (CECD) ultrasound was performed before and 7 and 14 d after dutasteride treatment. Contrast-enhanced targeted biopsies (5) were performed into hypervascular areas of the peripheral zone only. Subsequently, a second investigator performed 10 systematic biopsies of the prostate in a standard spatial distribution guided by conventional grey-scale ultrasonography on a Combison 530MT unit. Results: Dutasteride reduced prostatic blood flow in benign prostatic tissue, whereas in prostate cancer areas blood flow was still observed after a 14-d course of dutasteride intake. A reduction of blood flow was observed even after 7 d. Maximum flow reduction was observed after 14 d. Twelve patients (33%) of our cohort were found to have suspicious blood flow and prostate cancer and six cancers (17%) were detected solely by targeted contrast-enhanced biopsy. Conclusion: Premedication with dutasteride seems promising to improve prostate cancer detection by using CECD ultrasound. # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, Medical University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria. Tel. +43 512 50424811; Fax: +43 512 50424873. E-mail address: michael.mitterberger@uibk.ac.at (M. Mitterberger). 0302-2838/$ see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.eururo.2007.02.031
european urology 53 (2008) 112 117 113 1. Introduction Systematic prostate biopsy under ultrasound (US) guidance is the preferred diagnostic method for prostate cancer detection [1]. However, US-guided detection of prostate cancer is limited by the inability of conventional grey scale and Doppler sonography to adequately distinguish benign and malignant prostate tissue [2,3]. In several recently published papers, an improved detection of prostate cancer based on contrast-enhanced colour Doppler (CECD) over grey scale sonography was reported [4,5]. Because of the increased local angiogenesis associated with cancer of the prostate, improved cancer detection may be achieved on the basis of the CECD blood flow characteristics of prostate cancer [4,5]. But prostatitis and benign prostatic hyperplasia (BPH) are also associated with increased CECD flow. Dutasteride (Avodart 1 ; Glaxo-Smith-Kline, Philadelphia, PA, USA), a type 1/2 5a-reductase inhibitor, is approved for treatment of symptomatic BPH. As recent studies suggest, dutasteride can reduce blood flow in normal prostate tissue and BPH. By reducing flow in normal tissues that responds to the 5a-reductase inhibitor it seems to be possible to improve differentiation between benign tissue and cancer in the prostate [6,7]. The theory was based on the fact that dutasteride should reduce blood flow in normal, benign prostate tissue, whereas blood flow in cancer should not be influenced and therefore prostate cancer detection should be improved. The primary objectives were to demonstrate a qualitative reduction in the CECD flow signal from normal prostate after treatment with dutasteride and to further determine the minimum length of treatment necessary to inhibit CECD flow in the normal prostate and in BPH tissue. Finally, we hoped to demonstrate that the identification of malignant tissue by increased CECD flow patterns can be improved after treatment with dutasteride. Therefore, the goal of this study was to assess the effect of premedication with dutasteride on prostatic blood flow prior to prostate biopsy and the impact on prostate cancer detection. 2. Patients and methods 2.1. Study patients We examined 36 consecutive asymptomatic screening male volunteers with a serum total prostate-specific antigen (PSA) level 1.25 ng/ml and a free-to-total PSA ratio <18% (Tyrolean PSA Screening Project). Digital rectal examination was not part of the screening process in this study, although it was done directly before biopsy. The patients were 41 77 yr of age (mean, 56 yr). Study exclusion criteria were active urinary tract infection or contraindications to the US contrast agent Sonovue TM (Bracco, Milano, Italy). The study was approved by our institutional review board and written patient informed consent was obtained before the examination. 2.2. Medication Dutasteride capsules (0.5 mg) were given to patients in 2-wk 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. 2.3. US procedure US was performed with the patients in the lithotomy position with a Sequoia system (Siemens Medical Systems, Mountain View, CA, USA) 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 maximise the visualisation of colour flow within the prostate without producing colour noise in stationary tissue. The same settings were used during followup examinations. First the CECD US flow within the whole prostate was assessed as described by Leventis et al [8]. Then the flow pattern was divided in radial or irregular and into symmetrical or asymmetrical flow. Than CECD US flow within the prostate was subjectively scored during each study. Flow was scored by using a 4-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 dutasteride/d 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. 2.4. Biopsy procedure The night before biopsy all participants began a 5-d course of a fluoroquinolone antibiotic or appropriate alternative antibiotic if they had a fluoroquinolone allergy. A cleansing enema was administered on the morning of biopsy. Patients were instructed not to ingest aspirin or nonsteroidal anti-inflammatory agents for at least 10 d before biopsy. CECD and the SB were performed using a needle guidance device with the patient in the lithotomy position. One investigator used CECD imaging with an Acuson Sequoia 512 unit (Siemens Medical Solutions) fitted with an end-fire probe operating at a Doppler frequency of 9 MHz. Up to five targeted biopsy cores were obtained during intravenous injection of the US contrast agent Sonovue (Bracco), using a maximum dose of 2 ml. The contrast agent was prepared in standard fashion. Colour Doppler system presets were optimised based on experience to detect contrast-enhanced
114 european urology 53 (2008) 112 117 flow. Contrast-enhanced imaging was always performed before systematic biopsies (SBs) to avoid biopsy-induced hyperaemia on the contrast-enhanced imaging study. CECD was performed into a maximum of two hypervascular areas in the peripheral zone (PZ) only. No targeted biopsies were performed in the transition zone (TZ). This biopsy approach was done using a 9-MHz end-fire probe, which enables a single plane approach. Subsequently another investigator blinded to contrastenhanced findings performed 10 SBs in standard spatial distribution. This biopsy was guided by grey-scale US using an endorectal probe unit fitted with a biplane probe operating at a grey scale frequency of 7.5 MHz (BK-med, Copenhagen, Denmark). Biopsies were obtained without regard to prostate US appearance. Two biopsy cores per side were obtained from the apex area, including one medial and one lateral. Another biopsy core was obtained on each side from the lateral aspect of the mid prostate, one was obtained on each side from the posterolateral area at the base, and a final biopsy core was obtained from each side of the TZ. TZ biopsies were anterior biopsies in the mid prostate. Biopsies were obtained transrectally using an 18-gauge biopsy needle. Each biopsy core was reviewed by a pathologist and reported as cancer with an assigned Gleason score, or as prostatic intraepithelial neoplasia, inflammation, or benign prostatic tissue. The changes in prostatic blood flow and the impact on prostate cancer detection were evaluated. For statistical analyses the Wilcoxon matched-pairs signed rank test was used; p < 0.05 was considered to indicate a statistically significant difference. 3. Results 3.1. Biopsies Mean patient age was 56 yr (range: 41 74 yr), mean total PSA was 4.6 ng/ml (range: 1.4 8.0 ng/ ml), the mean free-to-total PSA ratio was 12.83% (range: 4 17.9%), and mean prostate volume was 35.5 ml (range: 11 175). 3.2. CECD flow suppression In all patients a suppression of CECD flow by at least one score was noted after 1 wk of dutasteride therapy ( p < 0.02). After 2 wk of dutasteride therapy CECD flow was further suppressed one score in all patients ( p = 0.03), as shown in Fig. 1. 3.3. Cancer detection In 12 patients (33.3%) of our cohort of 36 patients prostate cancer was found. Pathologic evaluation revealed that the areas of malignancy had a Gleason score of 6 in six patients, Gleason score of 7 in three patients, and a Gleason score of 8 in three patients. CECD-targeted biopsy revealed cancer in all 12 of these patients. SBs revealed the tumour in 6 of the 12 patients. Cancer was detected in 30 (17%) of 180 CECD-targeted biopsy cores and in 36 (10%) of 360 SB cores. In the 12 patients with cancer, conditional logistic regression analysis revealed that targeted cores were twice as more likely to be positive for cancer ( p = 0.027). Prostatitis was diagnosed at biopsy in 12 patients. None of these patients were also diagnosed with cancer. The rate of prostatitis detection was in SB cores was 40 of 360 (11%), whereas in CECD-directed biopsy prostatitis was diagnosed in 9 of 180 (5%). Dutasteride reduced prostatic blood flow in benign prostatic tissue, whereas in prostate cancer areas blood flow was still observed after a 14-d course of dutasteride intake. The sites of cancer were more obvious after dutasteride therapy (Fig. 1B and C). 3.4. Complications No adverse events were reported. No complications resulted from the medication, US examinations, or biopsy procedures. 4. Discussion Transrectal US-guided SB of the prostate is the standard technique for diagnosing prostate cancer [1]. Several clinical studies have demonstrated the efficacy of contrast-enhanced US imaging for the detection of prostate cancer [4,5]. In this study patients with an elevated PSA were pretreated for 2 wk with the dual 5a-reductase inhibitor dutasteride before systematic prostate biopsy and CECD-targeted prostate biopsy was performed. The results of this study demonstrate the qualitative reduction of prostatic blood flow after shortterm oral therapy with dutasteride. A reduction of blood flow was already observed after 7 d and a further reduction was observed after 14 d of medication intake. These results confirm the recent findings of Ives et al [9], who found a reduction in visible Doppler US flow in all areas of the prostate after short-term therapy with dutasteride. As in their study we believe that the 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]. A previous study correlated whole-mount prostatectomy specimens with contrast-enhanced imaging
european urology 53 (2008) 112 117 115 Fig. 1 Transverse ultrasound (US) images of prostate in 74-yr-old man with an elevated prostate-specific antigen level. Contrast-enhanced colour Doppler (CECD) US images through the midgland obtained (A) at baseline, (B) after 1 wk, and (C) after 2 wk of dutasteride therapy. The baseline images show increased CECD US flow at the right side of the gland with suspicion of prostate cancer. The posttreatment images show reduced overall CECD US flow after 1 wk and even absent after 2 wk of treatment. of the microbubble agent Sonazoid (Amersham Health, Oslo, Norway). Thirty-one foci of cancer were correlated between contrast-enhanced sonography and whole-mount pathologic inspection. Contrastenhanced imaging doubled the sensitivity for detection of cancer in the PZ of the prostate but did not improve the detection of inner gland cancer. The contrast-enhanced detection of cancers in the inner gland was limited by intense enhancement in areas of BPH. False-positive diagnoses of prostate cancer were suggested in both the inner and outer parts of the gland in areas of benign hyperplasia [10]. The results of this and other previous investigations have indicated that CECD US is only minimally better than conventional grey-scale US for distinguishing benign from malignant tissue [11]. The poor discrimination of benign from malignant tissue is due in part to the CECD signal arising from areas of benign disease such as BPH [12]. Therefore, given the association of false-positive areas of enhancement with BPH, one might expect to improve the specificity of CECD by pretreatment with a 5a-reductase inhibitor to suppress perfusion to areas of BPH. BPH nodules normally develop in the TZ or in the periurethral tissue, but BPH has also been identified at pathologic evaluation of the PZ [10,13]. In this small study, as mentioned above, 2-wk therapy with dutasteride reduced visible CECD flow in all areas of the prostate. It seems that dutasteride reduces
116 european urology 53 (2008) 112 117 prostatic blood flow in benign tissue, whereas cancerous areas are still hypervascular after a 14-d intake of dutasteride. Twelve patients (33.3%) in our cohort were found to have suspicious blood flow and prostate cancer, and six cancers (16.6%) were detected solely by CECD-targeted biopsy. Prostatitis is also often considered an important cause of false-positive results at color Doppler US imaging of the prostate [10]. Interestingly in the present study prostatitis was not a significant cause of false-positive diagnoses with contrast enhancement. These findings match previous reported data from Halpern et al [14]. Our result suggests that the CECD signal associated with prostatitis and also benign prostate tissues is suppressed by dutasteride. In a previous trial, 11 subjects before prostate biopsy were evaluated by grey scale, colour, and power Doppler at baseline and weekly for up to 3 wk while taking the 5a-reductase inhibitor dutasteride (0.5 mg/d) [9]. Doppler flow suppression occurred in all 11 subjects after 1 wk ( p < 0.01). Further suppression was noted after 2 wk in 8 subjects ( p = 0.04). Flow suppression was greatest in the PZ and least obvious in the periurethral zone. Cancer was detected in 20% (8 of 40) of targeted cores and 7.6% (5 of 66) of sextant cores. Cancer was detected in 4 subjects by targeted biopsy and in 3 of 4 by SB. In the 4 men with cancer, targeted cores were 5.9 times more likely to be positive ( p = 0.027). Selective suppression of flow in benign tissue was observed in 2 of the 4 men with cancer. They concluded that shortterm dutasteride therapy reduces Doppler US flow in the prostate and may improve depiction of hypervascular cancer. They used Doppler US for blood flow evaluation of the prostate, whereas in our approach CECD has been used. CECD has shown to be more sensitive to slow flow and flow in small vessels by increasing the signal-to-noise ratio. This might further explain the better differentiation between benign and malignant prostate tissue. Our study demonstrates the reduction of prostatic blood flow in normal prostate, BPH, and prostatitis after short-term oral therapy with dutasteride, whereas cancerous areas are still hypervascular after a 14-d intake of dutasteride. Therefore, premedication with dutasteride seems promising to improve prostate cancer detection by using CECD US. This study has several limitations of which only the main ones are discussed. This had only a small study population, intraobserver and interobserver variability was not evaluated, no correlations were made with final radical prostatectomy specimens, and the CECD blood flow rating was subjectively measured. In the SB approach TZ biopsies have been performed, although a previous study by Pelzer et al suggested that in participants of a PSA screening program TZ biopsies do not improve prostate cancer detection rate and are therefore unnecessary [15]. Further, only the short-term therapy over 2 wk with dutasteride is reported; long-term effects are unknown. Therefore, further studies are necessary. 5. Conclusions Premedication with dutasteride seems promising to improve prostate cancer detection by using CECD US. Conflicts of interest There is no conflict of interest. References [1] Aus G, Abbou CC, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol 2005;48:546 51. [2] Aarnink RG, Beerlage HP, De La Rosette JJ, Debruyne FM, Wijkstra H. Transrectal ultrasound of the prostate: innovations and future applications. J Urol 1998;159:1568 79. [3] Kravchick S, Cytron S, Peled R, Altshuler A, Ben-Dor D. Using gray-scale and two different techniques of color Doppler sonography to detect prostate cancer. Urology 2003;61:977 81. [4] Frauscher F, Klauser A, Volgger H, et al. Comparison of contrast enhanced color Doppler targeted biopsy with conventional systematic biopsy: impact on prostate cancer detection. J Urol 2002;167:1648 52. [5] Pelzer A, Bektic J, Berger AP, et al. Prostate cancer detection in men with prostate specific antigen 4 to 10 ng/ml using a combined approach of contrast enhanced color Doppler targeted and systematic biopsy. J Urol 2005;173: 1926 9. [6] Donohue JF, Sharma H, Abraham R, Natalwala S, Thomas DR, Foster MC. Transurethral prostate resection and bleeding: a randomized, placebo controlled trial of role of finasteride for decreasing operative blood loss. J Urol 2002;168:2024 6. [7] Hochberg DA, Basillote JB, Armenakas NA, et al. Decreased suburethral prostatic microvessel density in finasteride treated prostates: a possible mechanism for reduced bleeding in benign prostatic hyperplasia. J Urol 2002;167:1731 3. [8] Leventis AK, Shariat SF, Utsunomiya T, Slawin KM. Characteristics of normal prostate vascular anatomy as displayed by power Doppler. Prostate 2001;46:281 8. [9] Ives EP, Gomella LG, Halpern EJ. Effect of dutasteride therapy on Doppler US evaluation of prostate: preliminary results. Radiology 2005;237:197 201.
european urology 53 (2008) 112 117 117 [10] Halpern EJ, McCue PA, Aksnes AK, Hagen EK, Frauscher F, Gomella LG. Contrast-enhanced US of the prostate with Sonazoid: comparison with whole-mount prostatectomy specimens in 12 patients. Radiology 2002;222:361 6. [11] van Moerkerk H, Heijmink SW, Hulsbergen-v.d. Kaa CA, Barentsz JO, Witjes JA. Computerized three-dimensional localization of prostate cancer using contrast-enhanced power Doppler and clustering analysis. Eur Urol 2006; 50:762 8, discussion 768 9. [12] Halpern EJ, Rosenberg M, Gomella LG. Prostate cancer: contrast-enhanced US for detection. Radiology 2001;219: 219 25. [13] Hamper UM, Sheth S, Walsh PC, Holtz PM, Epstein JI. Stage B adenocarcinoma of the prostate: transrectal US and pathologic correlation of nonmalignant hypoechoic peripheral zone lesions. Radiology 1991;180:101 4. [14] Halpern EJ, Ramey JR, Strup SE, Frauscher F, McCue P, Gomella LG. Detection of prostate carcinoma with contrast-enhanced sonography using intermittent harmonic imaging. Cancer 2005;104:2373 83. [15] Pelzer AE, Bektic J, Berger AP, et al. Are transition zone biopsies still necessary to improve prostate cancer detection? Results from the Tyrol Screening Project. Eur Urol 2005;48:916 21, discussion 921.