Contrast-Enhanced Ultrasound and Prostate Cancer; A Multicentre European Research Coordination Project

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1 european urology 54 (2008) available at journal homepage: Review Prostate Cancer Contrast-Enhanced Ultrasound and Prostate Cancer; A Multicentre European Research Coordination Project Margot Wink a, Ferdinand Frauscher c, David Cosgrove b, Jean-Yves Chapelon d, Leo Palwein c, Michael Mitterberger c, Chris Harvey b, Olivier Rouvière d, Jean de la Rosette a, Hessel Wijkstra a, * a Department of Urology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands b Department of Radiology, Imperial College, London, United Kingdom c Department of Uro-Radiology, University Hospital, Innsbruck, Austria d INSERM U556, Lyon, France Article info Article history: Accepted June 12, 2008 Published online ahead of print on June 20, 2008 Keywords: Prostate carcinoma Microbubbles Ultrasound Abstract Context: Contrast-enhanced ultrasound is a real-time imaging technique with the capability of visualizing perfusion patterns. Since tumour growth is associated with changes in vascularisation, this modality is under research for imaging of various tumour types. Studies have shown promising results for the diagnosis of prostate cancer for various imaging techniques; however, the exact value of each technique is still unclear. Objective: To determine the value of contrast-enhanced ultrasound (CEUS) in the detection, localisation, and follow-up of treatment for prostate cancer. Evidence acquisition: In the period , research in four European centres regarding CEUS of the prostate was coordinated in a combined program. This paper describes and combines the results of these studies. Evidence synthesis: Various techniques were developed and researched during the period of this program. Studies showed that prostate cancer could be visualized and localized in up to 78%. Visualization of the tumour enabled better detection; targeted biopsies lead to fewer biopsies per session without loss of detection rate. A combined approach offered the highest detection rate. CEUS could be used to visualize the effects of high-intensity focussed ultrasound and hormonal therapy for prostate cancer with success, and identified patients with an early relapse. Unfortunately, pretreatment evaluation could not identify the nonresponders beforehand. Conclusions: This research project was a first step towards routine use of CEUS in the clinical detection and follow-up of prostate cancer; and new combined studies are initiated. # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Academic Medical Centre, University of Amsterdam, Department of Urology, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel ; Fax: address: h.wijkstra@amc.uva.nl (H. Wijkstra) /$ see back matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. doi: /j.eururo

2 european urology 54 (2008) Introduction 1.1. Diagnosis The diagnosis of prostate cancer (PCa) is far from optimal [1]. Currently, at least 10 biopsy cores are recommended for routine use in the PCa guidelines provided by the European Association of Urology [2]. The positive predictive value of biopsies based on prostate-specific antigen (PSA), digital rectal examination (DRE), and transrectal ultrasound (TRUS) is low and many unnecessary biopsies are performed [3]. Moreover, even in patients with low PSA values a significant number of PCa cases are found [4,5]. Therefore, the search for improvement of diagnostic techniques is a necessity. Several different approaches to improve detection are studied. Regarding tumour markers, the optimal cut-off value of PSA is still under investigation. Novel tumour markers in blood and urine have been researched, but no highly accurate and sensitive markers to replace PSA have been identified until now. A recent review concludes that various biomarkers under investigation are promising, but all still have to be validated [6,7]. When visualization of PCa is improved, the biopsy needle can be targeted to the centre of the tumour. This will lead to a change in biopsy strategies, and possibly better grading. Furthermore, better visibility of malignant tissue will probably also improve staging. If the exact location and volume of the tumour is known, treatment can be improved. Moreover, follow-up can be optimized if imaging can localize recurrence of malignant tissue. Detection and localisation of prostate tumours using greyscale ultrasound is poor, and TRUS is mainly used to guide systematic biopsies. In a screening program, it is stated that TRUS can be safely omitted as screening tool [8]. MR, PET-CT, and nuclear imaging modalities have been reported to have diagnostic value in local staging and detection of the tumour Background Tumour growth induces neovascularization [9], and an increased microvessel density is associated with the prognosis and progression of PCa, in terms of metastases, stage of disease, and disease-specific survival [10 12]. Therefore, visualization of the induced altered perfusion patterns may improve detection of cancer. Contrast-enhanced ultrasound imaging (CEUS) was developed to image perfusion [13,14]. Because of the high spatial and temporal resolution of ultrasound, detailed and real-time perfusion imaging became possible. Ultrasound contrast agents consist of small encapsulated gas bubbles that are administered intravenously and remain intravascular. Adding microbubbles as additional reflectors into the bloodstream increases the sensitivity of colour (CD) and power Doppler (PD) imaging. However, these techniques use relatively high US energy levels and, as a result, a large proportion of the microbubbles are destroyed as they are imaged [15]. During the last years, new imaging techniques have been developed that enable sensitive microbubble imaging even in the microvasculature, with lower destruction rates (Low mechanical index imaging). Nowadays, a long list of CEUS techniques is available, from harmonic imaging, using the nonlinear behaviour of microbubbles in an ultrasound beam, via pulse inversion techniques, using various pulses to isolate the nonlinear reflections, to even more specific imaging techniques that provide selective imaging of the signals reflected by the bubbles, cancelling out most of the tissue reflections. During the last decade, mainly European research groups have published promising results of CEUS for the diagnosis of PCa and for guiding biopsies. In 2000, a project was defined to coordinate single institute efforts on a European level. The goal was to improve diagnosis and treatment of PCa by coordination of the research. A project proposal was submitted for funding in the European Community s Sixth Framework Programme (FP6), and, in 2002, the project CONTRAST, QLRT : Contrastenhanced ultrasound imaging in the diagnosis and treatment of prostate cancer was granted. This manuscript reviews the achieved results of this European Community project in comparison to published data outside this research group. Based on this, a critical evaluation of CEUS is presented and the expectations for the future are discussed. 2. Methods The project was active during the period The project leaders are coauthoring this paper. There were four main project objectives: Achieve a critical mass by coordinating research efforts and pooling data Coordinate transrectal CEUS research in Europe Disseminate results Set up continuation of research after the end of the project. The project consisted of eight work packages (WP) as described in Table 1 and coordinated as shown in Table 2. During the course of the project, newer techniques were

3 984 european urology 54 (2008) Table 1 Description of individual research work packages WP1 WP2 WP3 WP4 WP5 WP6 WP7 WP8 Management Research coordination Correlation of imaging and whole prostate histology Impact of contrast-enhanced ultrasound imaging on biopsy protocols Treatment planning and tissue lesion characterisation Early response to treatment Novel microbubble specific ultrasound imaging Dissemination of results implemented in all centres. Various commercially available microbubble contrast agents and ultrasound machines were used. were detected. Unal et al [18] concluded that 3DPDCEUS was the best single diagnostic tool for the detection of PCa in a study including men with and without cancer. In a small series using micro vascular imaging (Philips), all T3 tumours could be visualised. These results are promising, but the clinical value should be tested in a diagnostic setting. Studies with the latest contrast specific imaging techniques have been performed, but not yet published, with varying outcomes. These data show an increased sensitivity for the detection of perfusion patterns. An example of a CEUS investigation using a contrast specific imaging and postprocessing technique (micro vascular imaging, Philips, Bothel) is shown in Fig Diagnosis: targeting 3. Results The outcomes of the clinical WPs are described below in the different subheadings, and an overview of the most important conclusions is presented in Table Diagnosis: localization Preoperative CEUS was correlated to the histology of resected prostates. Sedelaar et al [16] had already concluded in 2001 that transrectal three-dimensional power Doppler (3DPD) CEUS has the potential to visualize lesions with an increased micro vessel density. Discrimination between left- and rightlocalized tumours could be accurately performed in 78% using the same technique and off-line analysis by Goossen et al [17]. A large patient group was evaluated with 3DPDCEUS before radical prostatectomy and 68 79% of all tumour foci larger than 5 mm The main objective was to assess the value of CEUS targeted biopsies: Figs. 2 and 3. Frauscher et al compared CDCEUS targeted biopsy (CB) of the prostate using Levovist (Schering, Berlin) with gray scale ultrasound guided systematic biopsy (SB) [19]. Two hundred thirty male screening volunteers were included. The detection rate was 30%, including 56 (24.4%) by CB and in 52 (22.6%) by SB. Cancer was detected by CB alone in 17 patients (7.4%) and by SB alone in 13 (5.6%). The detection rate for CB cores (10.4% or 118 of 1,139 cores) was significantly better than for SB cores (5.3% or 123 of 2300 cores). CB in a patient with cancer was 2.6-fold more likely to detect PCa than SB. CB detected as many cancers as SB with fewer than half the number of biopsy cores. Pelzer et al thereafter investigated the impact of a combined approach of CB and SB on the PCa detection rate in men with prostate-specific antigen (PSA) 4.0 to 10 ng/ml [20]. They examined 380 screening volunteers and found that cancer was Table 2 Description of research areas per institution and related work packages Research area Main investigator Work packages Localisation studies. Correlation between contrast-enhanced ultrasound results and histology of the full mount specimen after radical prostatectomy. Biopsy studies. Correlation between imaging results and biopsy outcome. Impact of contrast-enhanced ultrasound on the biopsy protocol. Treatment studies. Predictive value of contrast-enhanced ultrasound for treatment outcome of high intensity focused ultrasound of the prostate. Early depiction of residual cancer after treatment. Technique studies. Developments in hardware and software for the improvement of contrast-enhanced ultrasound, specifically of the prostate. The Netherlands 1, 2, 3, 7, 8 Austria 4, 8 France 5, 8 Great Britain 6, 8

4 Table 3 Summary of results of CEUS studies in this project Work package Papers Ref # Patients CEUS Technique Main results Diagnosis; localisation - correlation with radical prostatectomy Diagnosis; targeting - CEUS targeted biopsies Sedelaar, 2001 [16] 7 Contrast enhanced Power Doppler Left-right tumor discrimination was possible in all cases. 3D Power Doppler contrast ultrasonography has the potential to visualize lesions with increased MVD. Goossen 2003 [17] 29 Contrast enhanced Power Doppler Malignancies can be accurately localized in either the left or the right side of the prostate based on the time to maximum enhancement. Unal 2000 [18] 59 3D contrast enhanced Power Doppler The most suitable diagnostic predictor for prostate cancer was a combination of CEUS and PSA level. Unpublished data Contrast specific imaging More sensitive detection of microbubble refections, ongoing study correlation CEUS and radical prostatectomy. Frauscher 2002 [19] 230 Contrast enhanced Colour Doppler Same detection rate targeted biopsies requiring less biopsies in comparison with random biopsies. Pelzer 2005 [20] 380 Contrast enhanced Colour Doppler CEUS allows for the detection of lesions that cannot be found on gray scale ultrasound or random biopsies. Combined use of CECD and random biopsies: maximal detection of PC (37.6%). Mitterberger 2007 [21] 100 Contrast enhanced Colour Doppler CEUS targeted biopsy detected more cancers than random biopsies with a reduced number of biopsy cores. Mitterberger 2007 [22] 36 Contrast enhanced Colour Doppler The short term application of a 5-alpha-reductase inhibitor may be promising to improve cancer detection, by reducing prostatic blood flow in benign prostatic tissue. Mitterberger 2007 [23] 690 Contrast enhanced Colour Doppler CEUS targeted biopsy detected cancers with higher Gleason scores and more cancers than random biopsy. Pallwein 2008 [42] 20 Contrast specific imaging Preliminary results, further improvement prostate cancer detection. Frauscher Contrast enhanced Colour Doppler Preliminary results as presented during the EAU meeting in 2008, contrast enhanced Colour Doppler targeted biopsy is superior to systematic prostate biopsy in a screening population. Treatment Rouviere 2006 [24] 82 Colour Doppler Colour Doppler targeted biopsies after HIFU detect 4.4 times more cancers than random biopsies in patients who did not receive hormone therapy. Elckersley 2002 [27] 36 Contrast enhanced Colour Doppler Microbubble enhanced ultrasound can show early response to treatment. Vascular enhancement declined with therapy, similar to PSA. Sedelaar 2000 [28] 9 3D Contrast enhanced Power Doppler 3D-CE-PDU can determine the size of the defect of HIFU ablative therapy for prostate carcinoma. The absence of blood flow reflects affected tissue after HIFU treatment. Unpublished data Contrast enhanced Colour Doppler CEUS pre-treatment does not correlate with treatment outcome after HIFU. Unpublished data Contrast enhanced Colour Doppler Ongoing study: post-treatment CEUS probably will allow a better targeting of the biopsy and a better depiction and localization of residual cancer foci. Total # patients 3746 Studies related to the cooperation outside the time frame of the EC project are also included. These studies were the result of research during the preparation of the project or during the still existing cooperation after the period of official EC project duration. Furthermore we added in the table the most recent CEUS results as presented during the EAU annual meeting in Milan, Italy Of each study, the reference, the number of patients, the used imaging technique and the main result(s) are presented. european urology 54 (2008)

5 986 european urology 54 (2008) Fig. 1 An example of micro vascular imaging (MVI, Philips Medical, Bothel). On the left a contrast only image, in which the signals reflected from the tissue are cancelled out, so that only the signals reflected by the microbubble contrast agent remain. The investigation starts with a black screen. On the right side of the ultrasound image (left side of the prostate), an area with increased signal can be seen. This area was suspicious for cancer because of early enhancement and increased enhancement compared to the other side of the prostate and corresponded to a focus of PCa. On the right side of the image, the MVI image is shown. This technique uses postprocessing software to map contrast agent progression. Each new contrast agent signal is added to the starting image. This enables even better detection of abnormal or changed perfusion patterns. detected in 37.6%. The cancer detection rate for CB and for SB was 27.4% and 27.6%, respectively. The cancer detection rate with the two 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). CB in a patient with cancer was 3.1-fold more likely to detect cancer than SB. However, the combined use of CB and SB allows for maximal cancer detection with a detection rate of 37.6%. Recently Mitterberger et al evaluated SB versus CB for the impact on Gleason score findings [21]. The study included 690 men and Sonovue (Bracco, Milan) was used. PCa was identified in 221 of 690 subjects (32%) with a mean PSA of 4.6 ng/ml. PCa was detected in 180 subjects (26%) with CB, and in 166 patients (24%) with SB. The Gleason score of all 180 cancers detected by CB targeted biopsy was 6 or higher (mean 6.8). The Gleason score of all 166 cancers detected by SB ranged between 4 and 6 (mean 5.4). CB detected significantly higher Gleason scores compared with SB. Further CB techniques may allow identification of more aggressive cancers, which is important for defining prognosis and deciding treatment. The effect of premedication of Dutasteride, a dual 5-alpha-reductase inhibitor, on prostatic blood flow prior prostate biopsy and the impact on PCa detection was assessed in Innsbruck. 36 patients (52 74 years) with elevated PSA (1.25 ng/ml and free-to-total ratio of <18%) were treated with Dutasteride 14 d prior to prostate biopsy. CDCEUS was performed before, 7 d after, and 14 d after treatment. Dutasteride has shown to reduce prostatic blood flow in benign prostatic tissue, whereas in PCa areas blood flow is still observed after a 14 d course. Twelve patients (33%) were found to have suspicious blood flow and PCa, and six cancers (17%) were detected solely by targeted contrast-enhanced biopsy [22]. In a recent prospective trial from Innsbruck, the previous findings were confirmed. The chance to find cancer in a targeted biopsy core was significantly higher than in a random biopsy core. Moreover, the total detection rate for five targeted biopsies alone was higher than for 10 random biopsies [23] Pretreatment evaluation To study the possible prognostic factor of prostatic blood flow for the success of high-intensity focused ultrasound (HIFU), a study was initiated in Lyon [24]. After HIFU, in most patients, transrectal control

6 european urology 54 (2008) planned for a transrectal HIFU ablation of PCa were included in the study. They all underwent a preoperative CDCEUS examination before and after contrast injection (Levovist, Schering, Berlin). Dedicated software (PixelFlux, Chameleon-software, Germany) was used to calculate the colour pixel density and the mean velocity within the peripheral zone, the transitional zone, and the periprostatic tissues. Six mo after HIFU treatment, random ultrasound-guided control biopsies were obtained in 31 patients. The uniformity of the tissue destruction observed on each sextant control biopsy was assessed with a three point scale. This tissue destruction score was then compared to the preoperative CDCEUS data. In the 182 sextants, tissue destruction score was 0 in 111, 1 in 27, and 2 in 44. Unfortunately, this score did not correlate with the preoperative CD findings in any region of interest, either before or after contrast injection Treatment effect Fig. 2 A 55-year-old man with prostate-specific antigen of 3.6 and Gleason 7 cancer in the left base of the prostate, only found by contrast-enhanced targeted biopsy. A. Conventional gray scale transverse image does not show any suspicious lesion. B. Only contrast-enhanced colour Doppler transverse image shows increased flow associated with the cancer. biopsy obtained 3 6 mo after treatment shows uniform tissue destruction throughout the gland. However, in some patients, incomplete tissue destruction with unaffected islets of viable cells (whether normal or tumoural) are found. Differences in local blood flow might explain these differences in individual responses to the treatment (heat sink effect) [25,26]. Thirty-five patients Because of the possibility of detailed imaging of perfusion, CEUS was investigated for the follow-up of minimally invasive and medical treatment modalities that influence the perfusion of the prostate. In 2002 CEUS monitoring of hormonal treatment was described in a combined study (London, Nijmegen). Thirty-six men with PCa were studied at baseline and at intervals during treatment using Levovist (Schering, Berlin) enhanced Doppler CEUS imaging. Quantitative analysis demonstrated a decrease in CEUS signal over time and a strong correlation with changes in the mean PSA (r = 0.95, p < 0.001) was found. In four patients, Doppler indices did not fall with PSA: Two patients with the most marked discrepancy relapsed at 6 mo [27]. Before the start of this project, the effects of HIFU could be visualized in a study in which patients underwent a radical prostatectomy after HIFU treatment. The areas without perfusion could be Fig. 3 A 61-year-old man with prostate-specific antigen of 4.2 and Gleason 8 cancer in the left base. A. Conventional gray scale transverse image shows no focal lesion. B. Contrast-enhanced colour Doppler transverse image shows increased flow in the left base, corresponding to the cancer. C. Also contrast-enhanced power Doppler transverse image shows increased flow corresponding to the cancer.

7 988 european urology 54 (2008) demarcated and treatment effects correlated with three-dimensional PDCEUS findings [28]. The presence of residual cancer after HIFU ablation of the prostate is usually diagnosed by random prostate biopsy taken routinely and in the event of significantly increased PSA [29,30]. However, since residual cancer can be efficiently treated by a second HIFU application or by radiation therapy, there is a need for an early diagnosis and localisation of residual tumour foci. In a study published in 2004, CD-guided sextant biopsies were obtained in 82 patients who had undergone prostate HIFU ablation for cancer, 24 of whom had hormone therapy before, CD findings were compared with biopsy results. Results showed that CD was a significant independent predictor of the biopsy results in patients without history of hormone therapy, with CD-positive sites being 4.4 times more likely to contain cancer at biopsy than CD-negative sites. However, CD was inaccurate in patients who had previously received hormone therapy. Moreover, CD sensitivity remained low in the overall study population, with only 38% of the sites with residual cancer showing positive CD findings [31]. These studies were performed without contrast media; a new study, described in the discussion, has started using CDCEUS. 4. Discussion 4.1. Localisation and detection Correlation between histology and CEUS regarding tumour localisation is promising, and improvement of techniques led to increase of detection. Strohmeyer et al have published comparable results to the ones presented here regarding CEUS correlation with radical prostatectomy specimens [32]. Halpern et al also correlated the CEUS findings using a harmonic imaging method to histology and found five more foci of cancer in addition to the eight out of 30 that were found using noncontrast ultrasound. However, seven false positive foci were detected [33]. Moerkerk et al used an automated 3D CDCEUS calculation and found a 65% correlation between the processed images and presence of malignancy. They conclude that the used clustering analysis can be of value in biopsy sessions [34]. Other imaging techniques under investigation for visualisation of PCa are MRI, PET/CT, and elastography ultrasound. A recent review concluded that no PET or PET/CT studies with a large number of patients and tissue confirmation exist and thus further investigations are required [35]. Regarding MRI more data are available. Especially functional MRI techniques are promising in the local staging [36,37]. A large meta-analysis found a maximum joint sensitivity and specificity for the detection of extracapsular extension of 64% [38]. However, a large heterogenicity exists in the available MRI literature, with sensitivity for detection varying between 37 90% [39]. Furthermore, a recent report shows that detection of tumour recurrence is possible using dynamic contrast-enhanced MRI [40]. Kim et al recently concluded in a review paper that 3 Tesla MR is not expected to substantially improve PCa localisation. However, the addition of specific techniques, such as spectroscopy, to conventional sequences at 3 T might improve diagnostic accuracy [41]. The main advantage of ultrasound is the easy accessibility and the possibility to take biopsies during the investigation. Elastography was able to detect 88% of the cancer foci in a study that correlated ultrasound results to radical prostatectomy specimens. Elastography guided biopsies showed a 2.9-fold higher detection rate than random biopsies in a group of 230 screening volunteers [42]. The effect of CEUS on the prostate biopsy protocol and detection rate was extensively investigated. From our studies, we concluded that a clear association between contrast enhancement in the prostate and the diagnosis of clinically significant PCa exists. It was shown that the sensitivity for PCa diagnosis is increased by CEUS targeted biopsy. Fewer biopsies are needed to accomplish the same detection rate. These findings were confirmed by the results of Roy et al, who found an increase in sensitivity for the detection of cancer using CDCEUS [43]. The Halpern group used various greyscale and harmonic CEUS techniques. A study comprising 301 patients found a significantly higher detection rate in CEUS targeted biopsies than in random biopsies [44]. Finally, combined results of 2008 men from the screening group in Innsbruck as presented at the EAU meeting in March 2008 clearly confirm earlier data [45]. Prostatitis and benign hyperplasia may cause falsepositive foci of enhancement [33]. Therefore, based on our preliminary experiences, the short-term application of a 5-alpha-reductase inhibitor may be promising to improve PCa detection, by reducing prostatic blood flow in benign prostatic tissue. The sensitivity and specificity for the detection of the reflections of the microbubbles increased during the development of CEUS. Newer, contrast-specific techniques were implemented in all centres. Preliminary results presented by Pallwein et al show a further increase in cancer detection rate using one of the recently developed contrast specific imaging techniques, contrast pulse sequence imaging [42].

8 european urology 54 (2008) Improved visualisation of the tumour may not only lead to increased detection, but also to better Gleason grading and staging. One could imagine that a higher detection rate might lead to a higher percentage of clinically insignificant cancers; however, our results show that cancers found by means of targeted biopsy have a higher mean Gleason score than the ones found by random biopsies Follow-up After diagnosis, various treatments can be chosen, dependant on tumour size, grade, and extension. Minimally invasive and medical treatment modalities, such as HIFU and cryotherapy are being investigated. Because the tumour remains in situ, the evaluation of success and the follow-up of these modalities rely on PSA and imaging. Regarding HIFU, it could be concluded that CD-guided biopsy cores should be obtained to increase the sensitivity of residual cancer detection, at least in patients with no history of hormone therapy. It may be possible to further improve CD sensitivity in depicting residual cancer by using ultrasound contrast media and by optimizing the delay of post-hifu biopsy. HIFU ablation creates a coagulation necrosis and a devascularisation of the target volume [28,46]. Necrosis is gradually replaced by fibrosis and blood flow reappears in the treated volume in a centripetal way, within 3 5 mo. At control biopsy 3 6 mo after HIFU, the prostate is vascularised again, which may hinder the depiction of hyper-vascular residual cancer. Because very early post-hifu biopsy may be difficult to interpret on microscopy, a one-month delay was chosen. In a new study, CDCEUS is performed one day and one month after HIFUablation. During the last examination, biopsy cores are taken both in residual hyper vascular sites and in apparently totally devascularised areas. The biopsy results will be compared to the CDCEUS findings. This probably will allow a better targeting of the biopsy and a better localisation of residual cancer foci. An example is shown in Fig. 4. Because not all patients react to HIFU, CEUS as a prognostic factor for the treatment success has been investigated. Unfortunately, the CEUS outcomes did not correlate with the presence of vital tissue. Possibly the thermal gradient achieved with HIFU is too high for the blood flow to induce significant cooling, or the statistical power of the study was not sufficient to demonstrate the role of blood flow. The quantification of blood flow with CDCEUS remains difficult, even with the use of automated software. Moreover, because of the shrinkage of the prostate after HIFU, the correlation between preoperative imaging findings and postoperative biopsy is difficult. A recent study has shown that patients with a postoperative PSA nadir >0.2 ng/ml (a recognized predictor of poor outcome [47]) had a significantly higher preoperative prostate blood flow than patients with a postoperative PSA nadir <0.2 ng/ml [48]. This finding suggests that blood flow does play a role in the outcome of HIFU prostate ablation. However, the best way to quantify this blood flow preoperatively remains to be defined Critical notes More than 3000 CEUS studies have been carried out in the course of this project and no serious adverse events have occurred as a result of contrast administration. The most commonly mentioned minor side-effects of the used contrast media are alteration of taste, general or facial flush, and local pain at the injection site, and the technique is considered safe [49] as long as some recommendations are taken into account [14]. The newer techniques use very low mechanical index imaging, which further reduces the risk of any unwanted effects. Disadvantages of CEUS are extra time and additional costs. Preparing the contrast medium takes about 30 s and the investigation itself has a maximum duration of 4 min; the lifetime of the contrast medium. Including the handling time of possible extra biopsies and the preparation of the patient, the total investigation time of a prostate ultrasound study in our research setting increased with 5 10 min. Furthermore, as is the case in all ultrasound studies, this technique is operatordependant and a learning curve will definitely apply. In conclusion, a CEUS investigation is safe, but will account for extra investigation time, additional extra costs, and a learning curve. However, this is the case for a research setting. In the future, the extra time and costs might be less, because fewer biopsies will be required. Furthermore, all our detection-studies were carried out in a screening situation and might not be completely transferrable to a regular clinical situation. For now, CEUS enables visualization of PCa, but sensitivity and specificity are still not high enough to be able to avoid systematic random biopsies. However, targeted biopsies added to a random protocol do increase detection rate. The ability of CEUS to visualize perfusion in an organ that has limited blood flow enables visualization of various medical and minimally invasive treatment effects. Diagnosis and follow up of PCa remain challenging, but CEUS is an addition to the existing modalities,

9 990 european urology 54 (2008) Fig. 4 Transrectal ultrasound images obtained in a 74 year-old patient with local recurrence of prostate cancer after radiation therapy. This local recurrence had been treated by HIFU ablation one month before. A. Power Doppler image showed limited blood flux in the central gland of the prostate (arrow), suggesting that this area had not been totally destroyed by the HIFU ablation. B. Simultaneous acquisition of a low mechanical index ultrasound image (right side of the screen) and of a contrast ultrasound image (left side of the screen) 30 sec after bolus injection of 4.8 ml of Sonovue. The HIFU-induced coagulation necrosis was clearly seen as a devascularized area with no contrast enhancement (straight arrows). The anterior part of the left lobe showed intense enhancement on contrast image (arrowheads), suggesting it had not been destroyed by HIFU. Obtaining biopsy from that anterior territory might increase the sensitivity of residual cancer detection. Note that the devascularized area extended into the periprostatic tissues (curved arrow). which deserves a role in PCa management and still needs further investigation. Based on the goals written down in the original project plan, one could state that these were not achieved. During the project duration, no large multicentre studies were initiated, and at the end of the project period, CEUS does not yet have any role in the routine clinical practice. However, we believe that we made a first step. Together with the partners involved in this project, and together with major ultrasound and contrast companies in this field at his moment, initiatives are implemented which will make a difference in the nearby future. What can we expect in the near future? Many studies are still ongoing in each of the involved centres and new results will soon be available. A large prospective multicentre study will be initiated. The goal is to prove that currently available

10 european urology 54 (2008) CEUS techniques can be used to diagnose PCa and that CEUS targeted biopsies are superior as compared to systematic biopsies and therefore diagnosis will improve with fewer biopsy cores. Companies and research groups are developing new CEUS techniques, which have the potential to further improve CEUS. Furthermore, a new generation of microbubbles is under investigation and especially targeted microbubbles seem promising for the future. And, last but not least, drug and gene delivery with the help of microbubbles is under investigation in several research centres. We believe that CEUS in potential offers added value to the entire PCa care cycle, by adding a sensitive imaging modality. For now, however, the additional value has not yet been established. If multicentre approaches confirm the available results, diagnosis but also choice of treatment and follow-up of PCa could improve. Author contributions: Hessel Wijkstra had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Wink, Wijkstra. Acquisition of data: Wink, Pallwein, Mitterberger, Harvey, Rouviere. Analysis and interpretation of data: Wink, Pallwein, Mitterberger, Harvey, Rouviere, Frauscher, Cosgrove, Chapelon, Wijkstra. Drafting of the manuscript: Wink, Wijkstra, Chapelon, Cosgrove, Frauscher. Critical revision of the manuscript for important intellectual content: Wijkstra,Chapelon, Cosgrove, Frauscher, de la Rosette. Statistical analysis: None. Obtaining funding: Wijkstra, Cosgrove, Frauscher, Chapelon. Administrative, technical, or material support: None. Supervision: Wijkstra. Other (specify): None. Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: This study was funded by the European Community s Sixth Framework Programme (FP6). Funding/Support and role of the sponsor: Design and conduct of the study. References [1] Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, CA Cancer J Clin 2007;57: [2] Heidenreich A, Aus G, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol 2008;53: [3] Norberg M, Egevad L, Holmberg L, Sparen P, Norlen BJ, Busch C. The sextant protocol for ultrasound-guided core biopsies of the prostate underestimates the presence of cancer. 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12 european urology 54 (2008) Editorial Comment on: Contrast-Enhanced Ultrasound and Prostate Cancer; A Multicentre European Research Coordination Project Anurag K. Singh University at Buffalo School of Medicine, Department of Radiation Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, United States Anurag.singh@roswellpark.org Prostate-specific antigen testing has allowed for the detection of clinically insignificant prostate cancers that are unlikely to progress [1]. Detection, regardless of clinical significance, usually leads to aggressive treatment [2]. Since aggressive therapy carries attendant morbidity [3,4], it is critical to (1) determine which men are unlikely to progress to clinical significance and (2) evaluate methods to reduce treatment-related toxicity and/or to improve efficacy. Improved imaging that distinguishes benign from malignant prostate tissue would greatly advance both of these critical aims. Despite the potential of imaging, routinely employed imaging technologies (computed tomography, positron emission tomography, ultrasound, and magnetic resonance imaging) are not consistently able to differentiate benign from malignant tissues within the prostate. Development of methods to enhance standard imaging has been impeded by limitations of research funding and appropriate patients available for study. A multi-institutional design, while increasing the potential number of patients, is complicated by a multitude of factors including funding, initial periods of operator dependence, intellectual property rights, data sharing, continuing evolution of the technology during the study period, and parochial interests such as institutional prestige or individual career advancement. In the context of such impediments, Wink et al [5] are to be lauded for their efforts to accumulate data on contrast-enhanced ultrasound (CEUS) in a concerted, multi-institutional manner. These efforts produced several publications, as referenced in the paper, from individual institutions. In addition, the pooled analysis provides valuable safety, operator dependence, and time/cost data derived from a remarkable number (>3000) CEUS studies. Ultimately, the authors concede they have not yet met their stated goal of bringing CEUS into routine practice. Although the ultimate utility of CEUS in routine practice remains unknown, this project may serve as a model of multi-institutional collaboration to advance prostate imaging. References [1] Klotz L. Active surveillance for prostate cancer: for whom? J Clin Oncol 2005;23: [2] Cooperberg MR, Broering JM, Kantoff PW, et al. Contemporary trends in low risk prostate cancer: risk assessment and treatment. J Urol 2007;178:S14 9. [3] Van Tol-Geerdink JJ, Stalmeier PF, Pasker-de Jong PC, et al. Systematic review of the effect of radiation dose on tumor control and morbidity in the treatment of prostate cancer by 3D-CRT. Int J Radiat Oncol Biol Phys 2006;64: [4] Hu JC, Elkin EP, Pasta DJ, et al. Predicting quality of life after radical prostatectomy: results from CaPSURE. J Urol 2004;171:703 7, discussion [5] Wink M, Frauscher F, Cosgrove D, et al. Contrastenhanced ultrasound and prostate cancer; a multicentre European research coordination project. Eur Urol 2008; 54: DOI: /j.eururo DOI of original article: /j.eururo