0022-5347/05/1736-1926/0 THE JOURNAL OF UROLOGY® Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION Vol. 173, 1926 –1929, June 2005 Printed in U.S.A. DOI: 10.1097/01.ju.0000158444.56199.03 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 ALEXANDRE PELZER,* JASMIN BEKTIC, ANDREAS P. BERGER, LEO PALLWEIN, ETHAN J. HALPERN, WOLFGANG HORNINGER, GEORG BARTSCH AND FERDINAND FRAUSCHER From the Departments of Urology (AP, JB, APB, WH, GB) and Radiology (LP, FF), Innsbruck Medical University, Innsbruck, Austria, and Department of Radiology, Thomas Jefferson University, Jefferson Prostate Diagnostic Center (EJH), Philadelphia, Pennsylvania ABSTRACT Purpose: Transrectal gray scale ultrasound guided biopsy is the standard method for diagnosing prostate cancer (PC). Improved cancer detection with ultrasound contrast agents is related to better detection of tumor vascularity. We evaluated the impact of a combined approach of contrast enhanced, color Doppler targeted biopsy (CECD) and systematic biopsy (SB) for the PC detection rate in men with prostate specific antigen (PSA) 4.0 to 10 ng/ml. Materials and Methods: We examined 380 screening volunteers with a total PSA of 4.0 to 10 ng/ml (percent free PSA less than 18). CECD was always performed before SB. Another investigator blinded to contrast enhanced findings performed 10 SBs. The cancer detection rate for the CECD, SB and combined approaches was assessed. Results: PC was detected in 143 of 380 patients (37.6%, mean total PSA 6.2 ng/ml). The PC detection rate for CECD and for SB was 27.4% and 27.6%, respectively. The overall cancer detection rate with the 2 methods combined was 37.6%. For targeted biopsy cores the detection rate was significantly better than for SB cores (32.6% vs 17.9%, p ⬍0.01). CECD in a patient with cancer was 3.1-fold more likely to detect PC than SB. Conclusions: CECD allows for the detection of lesions that cannot be found on gray scale ultrasound or SB. CECD allows for assessment of neovascularity associated with PC. However, the combined use of CECD and SB allows for maximal detection of PC with a detection rate of 37.6% in our patients with PSA 4 to 10 ng/ml. KEY WORDS: prostate; prostatic neoplasms; prostate-specific antigen; biopsy; ultrasonography, Doppler, color Transrectal gray scale ultrasound (US) guided biopsy is the standard method for diagnosing prostate cancer (PC) in patients with increased total prostate specific antigen (tPSA) and/or abnormal digital rectal examination. Various biopsy strategies have been devised to increase the diagnostic yield of prostate biopsy, including sampling visually abnormal areas, more lateral placement of biopsies, anterior biopsies and an increasing number of cores, ranging from 5 region sampling to saturation biopsies with up to 45 cores.1⫺4 Color Doppler imaging is another tool that may be used to improve biopsy performance. Especially when combined with a contrast enhancing agent, Doppler US is a reliable, sensitive and noninvasive method to show tumor blood flow and, therefore, it has an important role in diagnostic US. Increased microvascularity accompanies cancer growth. Neovascularity may be detectable by color Doppler imaging due to abnormal blood flow patterns in larger feeding vessels.5, 6 Others have noted the improved positive predictive value of color Doppler imaging for detecting PC but most agree that color Doppler targeted biopsy does not detect many cancers identified by systematic gray scale US guided biopsy.7, 8 Thus, gray scale US guided biopsy remains the standard of care. More recently US contrast agents have been used to improve cancer detection.9 Improved cancer detection with US contrast agents is related to the better detection of slow flow and flow in small vessels, that is tumor vascularity, through an increased signal-to-noise ratio compared with the conventional color Doppler technique.10 We evaluated the impact of contrast enhanced, color Doppler targeted biopsy (CECD) combined with systematic biopsy (SB) to compare the cancer detection rate of the 2 techniques and evaluate the overall cancer detection rate in this population. MATERIALS AND METHODS We examined 380 consecutive asymptomatic screening male volunteers with tPSA 4.0 to 10 ng/ml (free-to-total PSA less than 18%). Table 1 lists study population characteristics. Digital rectal examination was not part of the screening process in this study, although it was done directly before biopsy. Patient age was 41 to 77 years (average 60.7). Study exclusion criteria were clinical prostatitis within 1 month of biopsy, active urinary tract infection or contraindications to the US contrast agent SonoVue®. The night before biopsy all participants began a 5-day Submitted for publication August 9, 2004. * Correspondence: Department of Urology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria (telephone: ⫹43 512 504 24810; FAX: ⫹43 512 504 28365; e-mail: [email protected]). 1926 TABLE 1. Screening population characteristics Mean (range) No. pts PSA (ng/ml) %fPSA Complete PSA (ng/ml) Prostate vol (ml) * In 280 patients. 380 6.2 (4–10) 12.83 (4–18) 4.7 (0.79–25)* 35.54 (11–175) 1927 PROSTATE CANCER DETECTION USING COMBINED APPROACH Detection rate of combined methods was above 95% CI of CECD and SB, for which detection rate was 27.4% and 27.6%, respectively course of a fluoroquinolone antibiotic or appropriate alternative antibiotic if there was 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 5 days before biopsy. CECD and the SB were performed using a needle guidance device with the patient in the lithotomy position. Five targeted biopsy cores were obtained during intravenous injection of the US contrast agent SonoVue®, which amplifies the color Doppler signal up to 25 dB.11 The contrast agent was prepared in standard fashion and administered to a maximum dose of 4.8 ml. Color Doppler system presets were optimized based on experience to detect contrast enhanced flow. Contrast enhanced imaging was always performed before systematic biopsies to avoid biopsy induced hyperemia on the contrast enhanced imaging study. CECD were performed into a maximum of 2 hypervascular areas in the peripheral zone (PZ) only. No targeted biopsies were performed in the transitional 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 contrast enhanced findings performed 10 SBs in standard spatial distribution. This biopsy was guided by gray scale US using an endorectal probe unit fitted with a biplane probe operating at a gray scale frequency of 7.5 MHz. Biopsies were obtained without regard to prostate US appearance. Two biopsy cores per side were obtained from the apex area, including 1 medial and 1 lateral. Another biopsy core was obtained on each side from the lateral aspect of the mid prostate, 1 was obtained on each side from the posterolateral area at the base, most likely in the central zone, and a final biopsy core was obtained from each side of the TZ. TZ biopsies were anterior biopsies in the mid prostate.12 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. For statistical analyses the Mann-Whitney U test was used. All statistical calculations were performed using SPSS 10.0 software (SPSS, Chicago, Illinois) with p ⬍0.05 considered as statistically significant. The cancer detection rates of the 2 techniques were compared. We further evaluated the overall cancer detection rate. PC was detected in 143 of the 380 patients (37.6%) with a mean tPSA of 6.2 ng/ml (range 4.0 to 10). PC was detected in 104 of the 380 patients (27.4%) during CECD and in 105 (27.6%) during SB (see figure, table 2). Based on cancers detected by biopsy using either technique the sensitivity for cancer detection was 73.4% (105 of 143 cases) for targeted biopsy and 72% (104 of 143 cases) for SB (see figure, table 2). The overall cancer detection rate with the 2 methods combined was 37.6% (143 patients) with a mean tPSA of 6.2 ng/ml. The detection rate of the combined methods was above the 95% CI limit of CECD and SB (see figure). Based on the cancer detection per core performed by CECD (32.6% or 233 of 715 cores) the detection rate was significantly better for CECD than for SB (17.9% or 257 of 1,430 cores, p ⬍0.01, table 3). CECD in a patient with PC was 3.1-fold more likely to detect PC than SB. Mean patient age at CECD and at SB detected PC was 64.13 and 63.69 years, mean PSA was 6.1 and 5.9 ng/ml, and mean Gleason score was 5.9 and 6.07, respectively. Gleason score in all 143 patients diagnosed by contrast enhanced imaging and gray scale US was between 4 and 9. In contrast to CECD (2 cases), the systematic approach detected more cases with a Gleason score of 4 and 5 (7). Table 4 shows the distribution of Gleason scores in all 143 patients with cancer. Analysis by patient demonstrated no statistically significant difference in the overall cancer detection rate in the CECD and SB arms of our study (27.4% vs 27.6%). TABLE 2. Cancer detection rate of CECD vs SB SB Neg Pos Pos Total No. 237 39 38 66 275 105 Totals 276 104 380 PC was detected in 104 patients (27%) during CECD and in 105 (27.6%) during SB. TABLE 3. Detection rate by number of cores No. Cores Contrast Enhanced RESULTS Table 1 lists screening population characteristics. Mean patient age was 60.69 years (range 41 to 77), mean tPSA was 6.2 ng/ml, the mean free-to-total PSA ratio was 12.83% (range 4% to 18%) and mean prostate volume was 35.5 ml (range 11 to 175). No. CECD Neg Pos Neg 233 482 Gray Scale 257 1,173 Totals (%) 715 (32.60) 1,430 (17.90) CECD in patient with PC was 3.1-fold more likely to detect PC than SB (p ⬍0.01). 1928 PROSTATE CANCER DETECTION USING COMBINED APPROACH TABLE 4. Gleason score distribution Gleason Score 4 5 6 7 8 9 No. Gray Scale 3 4 25 5 1 No. Contrast Enhanced 2 0 31 5 1 No. Gray Scale ⫹ Contrast Enhanced 2 27 34 2 1 Totals (%) 38 (10.0) 39 (10.2) 66 (17.0) In contrast to CECD targeted biopsy (2 patients), SB detected more patients (2) with Gleason score 4 and 5. DISCUSSION Transrectal US guided prostate SB is the standard technique for diagnosing PC. Studies have shown that a single set of 6 biopsies may miss clinically detectable PC in 15% to 34% of men.12⫺14 Recently groups advocated a higher number of biopsy cores to improve cancer detection. However, Naughton et al reported no increase in cancer detection when comparing 6 vs 12 biopsy cores.15 Our results comparing 10 vs 14 cores demonstrated that there is no significant improvement in cancer detection by increasing the number of biopsy cores. To improve further our detection of PC and limit the number of biopsy cores per patient we introduced microbubble contrast agents to optimize the diagnostic value of transrectal color Doppler US. It has been demonstrated that tumors larger than 1 mm2 must recruit new blood vessels to grow larger.16 This neovascularity results in more blood flow but much of the flow is in small vessels less than 100 m. Conventional color Doppler US cannot detect flow in such small vessels because of the limited spatial resolution of US equipment and slow flow in these vessels. However, intravascular US contrast agents can enhance the back scattered echo from blood flow in small vessels.17 US contrast agents provide clear enhancement of the Doppler signal from the human prostate. There are few studies of contrast enhancement in the human prostate. Ragde et al reported on 15 patients in whom Echogen® was administered for enhanced color Doppler imaging.17 They concluded that contrast enhanced US may be a useful technique for imaging prostatic blood flow and it may enable the more accurate identification of malignant lesions. Bogers et al performed contrast enhanced, 3-dimensional power Doppler US in 18 cases suspicious for prostate cancer based on an increased tPSA of greater than 4.0 ng/ml or abnormal digital rectal examination.18 In 12 of 13 cases contrast enhanced US was considered suspicious for cancer. Contrast enhanced US showed 85% sensitivity and 80% specificity compared with the 38% sensitivity of unenhanced US. A limitation of this study is the small number of patients and the relatively high mean PSA of 18.6 ng/ml. In our series of 380 men cancer was detected by CECD and SB in 104 (27.4%) and 105 (27.6%), respectively. Although the detection rates were almost similar, for targeted biopsy cores (32.6% or 233 of 715) the detection rate was significantly better than for SB cores (17.9% or 257 of 1,430, p ⬍0.01, table 3) and CD in a patient with PC was 3.1-fold more likely to detect PC than SB. However, contrast enhanced imaging failed to detect 39 cancers (10.2%). There are some factors that might explain why contrast enhanced imaging missed several cancers. 1) Targeted biopsies were performed into hypervascular areas in the PZ. That means that TZ cancers, which represent about 21.7% of cancers, were not detected using this approach. 2) Since we used an end fire probe for targeted biopsies, it seems possible that this approach is less accurate than the sagittal approach, which was performed for SB. 3) Operator dependence seems to be higher for the targeted technique than for the systematic one. The reason why we did not perform targeted biopsies into Total No. 5 6 83 44 4 1 143 (37.6) the TZ is based on the fact that changes in benign prostatic hyperplasia often demonstrate hypervascularity that cannot be differentiated from the hypervascularity caused by malignant tissue. It might be possible that with new techniques, such as dynamic assessment of contrast agent enhancement, this problem will be overcome. However, this must be evaluated in further studies. The limitations of this study are different US systems and US probes. Thus, we cannot definitely exclude an overlap between SB and CECD biopsy cores. An advantage of the biplane probe used is related to the fact that it allows the simultaneous display of the transverse and sagittal planes. This seems to be helpful for exactly guiding SB, whereas CECD was performed with a single plane probe only. Furthermore, the sagittal approach has been shown to provide better core specimens than the transverse biopsy approach, which was used for targeted biopsies. However, resolution of the end fire probe is higher than that of the biplane probe used (frequency 9 vs 7.5 MHz). An important issue in our study was how we performed biopsy. We performed 10 systematic and 5 targeted biopsies, which is completely different than a study design comparing 10 vs 15 cores. The reason is that the 5 CECDs were performed in approximately 80% of 1 hypervascularized area of the PZ only. In a previous study we have observed that multiple cores from 1 hypervascularized area were more likely to detect cancer than fewer less cores from 1 hypervascularized area. Furthermore, since we have the Tyrolean PSA screening program, the majority of our patients with cancer had only 1 hypervascularized area. Multiple hypervascularized areas are more likely to be associated with prostatitis in our population.19 The increase in PC detection was mainly related to CECD, which can detect areas that cannot be seen on gray scale US and are often not included in the SB approach. CONCLUSIONS We clearly observed that CECD improves PC detection. This techniques allows the detection of lesions that cannot be found on gray scale US or SB. The reason is that CECD allows the assessment of neovascularity associated with prostate cancer. However, combined CECD and SB allows maximal PC detection with a detection rate of 37.6% in our patients with PSA 4 to 10 ng/ml. REFERENCES 1. Hodge, K. K., McNeal, J. E., Terris, M. K. and Stamey, T. A.: Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol, 142: 71, 1989 2. Eskew, L. A., Bare, R. L. and McCullough, D. 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