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Role of multiparametric magnetic resonance imaging (MRI) in focal therapy for prostate cancer: a Delphi consensus project Berrend G. Muller1, Willemien van den Bos1, Maurizio Brausi2, Francois Cornud3, Paolo Gontero4, Alexander Kirkham5, Peter A. Pinto6, Thomas J. Polascik7, Ardeshir R. Rastinehad8, Theo M. de Reijke1, Jean J. de la Rosette1, Osamu Ukimura9, Arnauld Villers10, Jochen Walz11, Hessel Wijkstra1,12 and Michael Marberger13 1 Department of Urology, AMC University Hospital, Amsterdam, The Netherlands, 2Department of Urology, EstenseS. Agostino Hospital, Modena, Italy, 3Department of Radiology, Cochin Hospital, Paris, France, 4Department of Urology, Molinette University Hospital, Turin, Italy, 5Department of Radiology, University College Hospital, London, UK, 6 Department of Urology, National Cancer Institute, Bethesda, MD, 7Department of Surgery/Urology, Duke University Medical Center, Durham, NC, 8Department of Urology/Radiology, Smith Institute for Urology, New York, NY, 9Department of Urology, University of Southern California, Norris Cancer Center, Los Angeles, CA, USA, 10Department of Urology, CHU Lille, University Lille, Lille, 11Department of Urology, Institut Paoli-Calmettes Cancer Center, Marseille, France, 12 Department of Electrical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands, and 13 Department of Urology, Medical University of Vienna, Vienna, Austria Objective To define the role of multiparametric MRI (mpMRI) for treatment planning, guidance and follow-up in focal therapy for prostate cancer based on a multidisciplinary Delphi consensus project. Materials and Methods mpMRI of the prostate. Standardization of imaging protocols is essential and mpMRIs should be read by an experienced radiologist. In the follow-up after focal therapy, mpMRI should be performed after 6 months, followed by a yearly mpMRI. mpMRI findings should be confirmed by targeted biopsies before re-treatment. An online consensus process based on a questionnaire was circulated according to the Delphi method. No consensus was reached on whether mpMRI could replace transperineal template saturation biopsies to exclude significant lesions outside the target lesion. Discussion points were identified by literature research and were sent to the panel via an online questionnaire in three rounds. Conclusions A face-to-face consensus meeting followed the three rounds of questions that were sent to a 48-participant expert panel consisting of urologists, radiologists and engineers. Participants were presented with the results of the previous rounds. Conclusions formulated from the results of the questionnaire were discussed in the final face-to-face meeting. Consensus was reached on a number of areas related to the conduct, interpretation and reporting of mpMRI for use in treatment planning, guidance and follow-up of focal therapy for prostate cancer. Future studies, comparing mpMRI with transperineal saturation mapping biopsies, will confirm the importance of mpMRI for a variety of purposes in focal therapy for prostate cancer. Results Consensus was reached in 41% of all key items. Keywords Patients selected for focal therapy should have biopsy-proven prostate cancer. Biopsies should ideally be performed after prostate cancer, focal therapy, multiparametric MRI, consensus BJU Int 2014; 114: 698–707 wileyonlinelibrary.com © 2013 The Authors BJU International © 2013 BJU International | doi:10.1111/bju.12548 Published by John Wiley & Sons Ltd. www.bjui.org Multiparametric MRI in focal therapy for prostate cancer Introduction Two decades ago, imaging of breast tumours had significant limitations and was unreliable for organ-preserving surgical treatments. Scoring protocols for breast x-ray imaging and, at a later stage, breast MRI were developed through formal attempts to establish agreement among experts on areas of uncertainty [1–3]. These attempts resulted in reduced interobserver variability and improved the positive predictive value of pathology from breast biopsy, which paved the way for lumpectomy (focal therapy of the breast). Nowadays, this is the most prevalent treatment for breast cancer, with an oncological survival rate similar to that obtained with radical treatment [4]. We are currently witnessing a similar development in prostate cancer care. Localized prostate cancer is traditionally managed by radical treatment of the complete organ or by active monitoring. The first option may result in undesirable side effects such as erectile dysfunction and urinary incontinence, whereas active surveillance may cause anxiety about tumour progression and under-treatment [5]. Improved imaging techniques and biopsy protocols have led to the early detection of small tumours, characterized by small cancer volume and low grade [6]. Concerns regarding over-treatment of these small tumours have introduced the concept of focal therapy, using a variety of selective ablation technologies. Focal therapy is defined as a treatment that aims to eradicate known cancer within the prostate and preserve uninvolved healthy prostatic tissue, and consequently genitourinary function, without compromising cancer control [7]. Currently, focal therapy techniques in prostate cancer include cryotherapy [8], high-intensity focused ultrasonography [9], laser ablation therapy [10], radiofrequency ablation [11], irreversible electroporation [12] and photodynamic therapy [13]. For these forms of treatment, the accurate identification, localization, demarcation and, ideally, grading of a lesion are essential. MRI has the potential to fulfill these basic requirements for focal therapy in prostate cancer, but until recently, the diagnostic performance of MRI was too low to implement the technology into the diagnostic evaluation leading to focal therapy; however, there is increasing evidence, coming from centres of excellence, to support an accurate diagnostic performance of MRI, provided that multiple sequences are used and that their outputs are combined in a so-called multiparametric MRI (mpMRI) [14]. These sequences include T1-weighted and T2-weighted imaging, dynamic contrast-enhanced (DCE) imaging, diffusion-weighted imaging (DWI) and magnetic resonance spectroscopic imaging (MRSI). Disagreement among experts in the field of uro-radiology about the conduct, interpretation, and reporting of mpMRI prohibited the reproduction of results and the formation of uniformly comparable literature on diagnostic accuracy and, hence, the formation of standardized guidelines [15]. Consensus projects were therefore initiated to reach consensus on recommendations for standardization of conduct, interpretation and reporting of prostate mpMRI for prostate cancer detection and localization [16–18]. These studies and their recommendations aimed to address the lack of guidelines and consensus by increasing the uniformity and diagnostic accuracy of mpMRI in prostate cancer. Imaging criteria in focal therapy for prostate cancer differ from the regular criteria in prostate cancer because the histological diagnosis has usually already been established, and imaging is therefore used to identify cancers amenable for focal therapy. The main diagnostic objective of mpMRI is the identification of the precise location of the tumour within the prostate and any other cancerous lesions other than the targeted tumour and, in particular, other high grade lesions. As the majority of the patients who undergo MRI have had a previous biopsy, biopsy artifacts are also an important issue. The other applications of mpMRI in focal therapy are the monitoring of the treatment itself, and follow-up to document treatment efficacy. The present paper reports the recommendations of a panel of experts who participated in a formal consensus process that was conducted according to the Delphi method. The consensus project aimed to define when prostate mpMRI should be applied and how it should be conducted and reported when used in focal therapy for prostate cancer. Materials and Methods Delphi Method The essence of the Delphi consensus method is to derive quantitative estimates through the qualitative assessment of evidence. Studies of widely different design and quality can be assessed. When published information is scarce, experts can make inferences using other data from similar contexts. Experts’ estimates are aggregated and fed back anonymously to all participants, who then review their initial responses in view of group-wide choices. This practice confers anonymity and allows opinions to be expressed free from peer group pressure. The Delphi consensus method was considered to be the most appropriate for our objectives. The method is most suited to topic areas when there is limited quality evidence to enable a ‘gold standard’ recommendation to be made. The Delphi method used for the present study included a series of three online surveys, in which panelists were presented with the results of the previous survey and in which the participants could add, modify, or delete questions for the next round. A face-to-face discussion panel followed this series of questionnaires. The Delphi method was applied in accordance with the reported literature [19–21]. Panel Selection On the basis of a systematic literature review on [Prostate Cancer] AND [Focal Therapy] AND [Multiparametric MRI] © 2013 The Authors BJU International © 2013 BJU International 699 Muller et al. Table 1 Delphi panel. Selected participants Profession Location 1 Hashim Ahmed 2 Jelle Barentsz 3 Maurizio Brausi 4 Peter Carroll 5 Jean-Yves Chapelon 6 Peter Choyke 7 François Cornud 8 Sébastien Crouzet 9 Theo de Reijke 10 Bob Djavan 11 Scott Eggener 12 Mark Emberton 13 Marc Engelbrecht 14 Jurgen Fütterer 15 Albert Gelet 16 Paolo Gontero 17 Rajan Gupta 18 Masoom Haider 19 Mukesh Harisinghani 20 Stijn Heijmink 21 Hedvig Hricak 22 Didier Jacqmin 23 J. Stephen Jones 24 Aaron Katz 25 Kirkham 26 Laurence Klotz 27 John Kurhanewicz 28 Nathan Lawrentschuk 29 Constantino Leonardo 30 Uri Lindner 31 Vibeke Løgager 32 Michael Marberger 33 Alessandro Napoli 34 David Penson 35 Peter Pinto 36 Thomas Polascik 37 Ardeshir Rastinehad 38 Jean de la Rosette 39 Olivier Rouvière 40 Georg Salomon 41 Peter Scardino 42 MichielSedelaar 43 Samir Taneja 44 Joachim Thüroff 45 Osamu Ukimura 46 SadnaVerma 47 Arnauld Villers 48 Jochen Walz Urologist Radiologist Urologist Urologist Engineer Radiologist Radiologist Urologist Urologist Urologist Urologist Urologist Radiologist Radiologist Urologist Urologist Radiologist Radiologist Radiologist Radiologist Radiologist Urologist Urologist Urologist Radiologist Urologist Radiologist Urologist Urologist Urologist Radiologist Urologist Radiologist Urologist Urologist Urologist Urologist/Radiologist Urologist Radiologist Urologist Urologist Urologist Urologist Urologist Urologist Radiologist Urologist Urologist University College Hospital London, London, UK Radboud University Hospital, Nijmegen, the Netherlands EstenseS. Agostino Hospital, Modena, Italy University of California, San Francisco, USA National Institute of Health and Medical Research, Paris, France National Cancer Institute, Bethesda, USA Cochin Hospital, Paris, France Edouard Herriot Hospital, Lyon, France AMC University Hospital, Amsterdam, the Netherlands New York University, New York, USA/University of Vienna, Vienna, Austria University of Chicago, Chicago, USA University College Hospital London, London, UK AMC University Hospital, Amsterdam, the Netherlands Radboud University Hospital, Nijmegen, the Netherlands Edouard Herriot Hospital, Lyon, France Molinette University Hospital, Torino, Italy Duke University Medical Center, Durham, USA Sunnybrook Hospital, Toronto, Canada Harvard Medical School, Boston, USA Dutch Cancer Institute, Amsterdam, the Netherlands Memorial Sloan Kettering Cancer Center, New York, USA University Hospital of Strasbourg, Strasbourg, France Cleveland Clinic, Cleveland, USA Winthrop Urology Hospital, New York, USA University College Hospital London, London, UK Sunnybrook Hospital, Toronto, Canada University of California, San Francisco, USA University of Melbourne, Melbourne, Australia University of Rome, Rome, Italy Princess Margaret Hospital, Toronto, Canada Copenhagen University, Hospital Herlev, Herlev, Denmark Medical University of Vienna, Vienna, Austria Sapienza University of Rome, Rome, Italy Vanderbilt-Ingram Cancer Center, Nashville, USA National Cancer Institute, Bethesda, USA Duke University Medical Center, Durham, USA Smith Institute for Urology, New York, USA AMC University Hospital, Amsterdam, the Netherlands Edouard Herriot Hospital, Lyon, France University of Hamburg Martini Clinic, Hamburg, Germany Memorial Sloan Kettering Cancer Center, New York, USA Radboud University Hospital, Nijmegen, the Netherlands NYU Langone Medical Center, New York, USA University Medical Center, Johannes Gutenberg University, Mainz, Germany Keck Medical Center of USC, Los Angeles, USA University of Cincinnati, Cincinnati, USA Lille University Hospital, Lille, France Institut Paoli-Calmettes, Marseille, France (and synonyms), experts in the field were selected. All experts published in the field of focal therapy for prostate cancer and/or mpMRI were selected by their peers. Fifty experts were approached, one declined and one retracted after the first round, resulting in 48 panelists (urologists, radiologists and engineers) from Europe, North America, Asia and Australia (Tables 1,2). Commercial bias was excluded through the use of institutional funds. Construction of the Questionnaire An online questionnaire, operated and designed using an online questionnaire program (http://www.SurveyMonkey 700 © 2013 The Authors BJU International © 2013 BJU International .com), containing 41 items was constructed between 28 January and 15 April 2013. This online questionnaire was presented to the panelists in three rounds between 15 April and 29 April 2013, each time with a 1-week interval used for analysis and construction of the subsequent round. Items discussed can be found in Tables 3–5. B.G.M. and W.v.d.B. designed the first round of questionnaires, under the supervision of M.M. and J.d.l.R., using the literature review as described in item 2.2. Questions were based on controversial items in the studies, or items on which evidence was lacking. All subsequent rounds were designed by the feedback from the participating panelists. Each round was analysed and graphically presented to the participants in the next round. Multiparametric MRI in focal therapy for prostate cancer Table 2 Panel characteristics. Specialties, % Urologist Radiologist Engineer Urology-Radiology Focal therapy experience, % High-intensity focused ultrasonography Cryotherapy Laser therapy Irreversible electroporation Photodynamic therapy Radiofrequency ablation Other Patients treated with focal therapy on a yearly basis Range Mean estimated number of patients Total estimated number of patients treated on a yearly basis by the panel 62.5 33.3 2.1 2.1 59.6 46.8 31.9 12.8 29.8 12.8 12.8 0–300 38.15 1793 Participants were asked to clarify per question whether they considered themselves sufficiently knowledgeable to answer. Face-to-Face Meeting Format The face-to-face meeting took place on 29 May 2013, in Noordwijk, the Netherlands. Participants from the online questionnaire were invited to join. Fifteen experts in urology and uro-radiology attended the meeting and are listed among the authors of this manuscript. All panel members also participated in the online series of questionnaires. During the meeting, the results from the online questionnaire were discussed in plenary sessions to draw conclusions from the acquired data. No new input was taken into consideration. A chairman (B.G.M.), with no financial disclosures to declare, was chosen to preside over the meeting. Interpretation of the Results Consensus on a topic was defined as >80% unanimity on the question regarding this topic in the online questionnaire. The participants in the discussion are listed in Table 1. Results The results of the questionnaires are shown in Tables 3–5. During the meeting, final conclusions were formulated based on the acquired data from the questionnaires. Questionnaire results were not altered and no new data were taken into account during the meeting. A summary of the questionnaire results and items discussed in the meeting is given below. Consensus was reached on 41% of the items. Patient Selection and Treatment Planning The panel agreed that mpMRI is currently the ideal imaging tool for focal therapy of prostate cancer. For patient selection, histologically proven prostate cancer is still considered crucial. In other words, the prostate cancer should be biopsy-proven before receiving any focal therapy. These biopsies should preferably be done after mpMRI. The panel reached a consensus that 3 Tesla is the recommended field strength for use in focal therapy. An endorectal coil is increasingly recommended at low field strengths (63.8% for 1.5 Tesla compared with high field strengths (34% for 3 Tesla). There was a strong consensus that a pelvic phased array coil was indispensable in prostate mpMRI. The panelists recommended the following sequences: T1-weighted, T2-weighted and DCE imaging, and DWI. The inclusion of MRSI in mpMRI was not supported by a large group (only 10.6%). The majority of the panel (68.1%) defined 0.5 mL as the lower limit of a reliable detection rate in Gleason 6 tumours. In Gleason 7 tumours, 23.4% of the panel defined 0.2 mL as the lower limit for detection, but still most participants (65.96%) defined 0.5 mL as the lower limit. On this topic there was a remarkable difference between urologists and radiologists (6.9 vs 50%, respectively, defined the lower limit as 0.2 mL). The panel strongly agreed that tumour location within the prostate influenced the diagnostic accuracy of mpMRI. The detection rate is most accurate for tumours in the peripheral zone. The detection rate of tumours on mpMRI seemed to be independent of prostate volume. There was a strong consensus that ideally, the MRI should be performed before prostate biopsies. If this was not possible, a post-biopsy interval period of 6–8 weeks should be considered to facilitate reliable images on mpMRI. No consensus could be reached on the question of whether mpMRI was an adequate alternative for transperineal template saturation biopsies for the exclusion of significant lesions outside the target lesion. A study comparing the diagnostic performance of mpMRI to template saturation biopsies should first be executed, with sufficient power to adequately demonstrate the ability of mpMRI to replace the role of template saturation mapping biopsies. Treatment Guidance Most panel members use TRUS as guidance for focal therapy. Of all panel members, 35.7% use MRI-guided focal therapy. Consensus was reached that, where real-time MRI monitoring of focal therapy is used, magnetic resonance thermometry is the best suitable technology (restricted to thermal ablation technologies). The panel stated that the standardization of conduct and reporting protocols was of paramount importance (100% consensus), but 40.5% of the panel members worked with a self-developed protocol, and 7.1% did not even use a standardized protocol for MRI reporting. This illustrates that standardization between centres is essential. Finally, the need for a specialized radiologist to report on prostate mpMRI was debated. All of the panel members agreed that a specialized radiologist was necessary for image acquisition, reading and reporting of prostate mpMRI. To become expert and to remain experienced, the radiologist © 2013 The Authors BJU International © 2013 BJU International 701 Muller et al. Table 3 Results regarding treatment planning. Which diagnostic tool do you recommend for focal therapy treatment planning? MRI mpMRI TRUS Histoscanning Three-dimensional plotting Transperineal saturation biopsies Other With mpMRI. which field strength do you recommend for use in focal prostate cancer treatment planning? 3 Tesla 1.5 Tesla There is no significant difference between the two I don’t know Do you recommend the use of an endorectal coil in prostate mpMRI at 1.5 Tesla? Yes No I don’t know Do you recommend the use of an endorectal coil in prostate mpMRI at 3.0 Tesla? Yes No I don’t know Is an endorectal coil indicated if the mpMRI is used for diagnosis of prostate cancer? Yes No I don’t know Is an endorectal coil indicated if the mpMRI is used for localization of small lesions for focal therapy treatment planning? Yes No I don’t know Are there any exclusion criteria for use of an endorectal coil in prostate mpMRI? (Multiple options possible) No, endorectal coil is always indicated In patients who are eligible for radiation therapy (since it deforms the prostate) When localizing small tumours for focal treatment targeting (since it deforms the prostate) In patients on active surveillance When patients can not tolerate the endorectal coil (haemorrhoids, colorectal surgery) Other I don’t know Is the use of a pelvic phased array coil indicated for prostate mpMRI. in focal therapy treatment planning (localizing small lesions) Yes, always (with or without endorectal coil) Yes, and always without an endorectal coil Yes, and always in combination with an endorectal coil No, never I don’t know Which mpMRI sequences do you recommend for prostate MRI? T1-weighted imaging T2-weighted imaging DCE DWI MRSI I don’t know In Gleason 6 tumours, what are the lower limits of detection on mpMRI, with respect to tumour size? 0.2 mL 0.5 mL 0.7 mL 1.0 mL 1.2 mL I don’t know In Gleason 7 tumours, what are the lower limits of detection on mpMRI, with respect to tumour size? 0.2 mL 0.5 mL 0.7 mL 1.0 mL 1.2 mL I don’t know 702 © 2013 The Authors BJU International © 2013 BJU International Overall, % Radiologists, % Urologists, % 26.1 80.4 23.9 0 6.5 19.6 15.2 35.71 92.86 14 0 0 7.14 0 23.3 73.3 30 0 10 26.7 16.7 80.9 4.3 12.8 2.1 81.25 0 18.75 0 79.31 6.9 10.34 3.45 63.8 29.8 6.4 87.5 12.5 0 48.28 41.38 10.34 34 59.6 6.4 31.25 62.5 6.25 34.48 58.62 6.9 42.6 55.3 2.1 62.5 37.50 0 31.03 65.52 3.45 51.1 46.8 2.1 75 25 0 37.93 58.62 3.45 12.8 27.7 17 23.4 23.4 12.8 8.5 12.5 37.5 18.75 31.25 68.75 18.75 0 13.79 20.69 17.24 20.69 51.72 10.34 13.79 72.3 14.9 6.4 0 6.4 75 12.5 12.5 0 0 68.79 17.24 3.45 0 10.34 85.1 93.6 85.1 90 10.6 2 93.75 100 81.25 100 18.75 0 79.31 89.66 86.21 83.33 6.9 3.4 8.5 68.1 4.3 8.5 2.1 8.5 6.25 75 0 6.25 6.25 6.25 6.9 69 6.9 10.3 0 6.9 23.4 66 2.1 4.3 0 4.3 50 50 0 0 0 0 6.9 75.9 3.4 6.9 0 6.9 Multiparametric MRI in focal therapy for prostate cancer Table 3 Continued. Does tumour location within the prostate influence the accuracy of prostate MRI? Yes No I don’t know Is the detection rate of prostate tumours on mpMRI dependent on prostate volume? (Multiple answers possible) No Yes, with increasing prostate size detection rate decreases Yes, with large amount of BPH, false positive rate increases I don’t know Is there a minimal time span between prostate biopsies and MRI to facilitate reliable images? Yes, 3 weeks Yes, 6 weeks Yes, 8 weeks Yes, 12 weeks Do you consider mpMRI of the prostate an adequate alternative to systematic template saturation biopsies in patient selection for focal therapy? Yes No I don’t know Do you consider prostate mpMRI at least as adequate as template saturation biopsies in patient selection for focal therapy? Yes, always Yes, but only in patients with Gleason 7 tumours, or higher Yes, but only if targeted biopsy confirms the diagnosis No, never If tumour location within the prostate influences the accuracy of mpMRI, then the detection rates for tumours are lowest, highest or intermediate in: the transition zone the peripheral gland the anterior gland should read at least 50 prostate mpMRI scans with pathological feedback per year. Treatment Follow-Up It was found that mpMRI was the preferred method of focal therapy follow-up (95.7% consensus). Furthermore, the majority of the panel supported the use of PSA, prostate biopsies and MRI-TRUS-guided biopsies in the follow-up of focal therapies for prostate cancer. Of the panel members 76.6% indicated that mpMRI could accurately identify tumour recurrence in the prostate. Regarding the follow-up schedule of mpMRI after focal therapy, no consensus was reached; nonetheless, 63.83% indicated that the first mpMRI should be performed 6 months after focal treatment. The performance of a baseline mpMRI immediately or 3 months after treatment was discussed, but this did not receive much support (17.0%). Equal support for both mpMRI every 6 months (51.1%) and every year (42.6%) was found for imaging intervals after initial imaging after focal therapy. In the face-to-face meeting, the panel agreed that mpMRI every year after treatment was sufficient. There was a strong agreement (89.4%) that definitive tissue destruction immediately after focal therapy results in a loss of enhancement on a DCE MRI. Furthermore, 67.4% of the panelists defined definitive tissue destruction as a loss of enhancement on DCE MRI, 6 months after treatment. Overall, % Radiologists, % Urologists, % 95.2 4.8 0 92.86 7.14 0 96.2 3.8 0 63.8 29.8 12.8 2.1 62.5 37.5 18.75 6.25 69 24.1 10.3 6.9 4.3 66 19.1 10.6 12.5 56.25 12.5 18.75 0 69 24.1 6.9 54.3 39.1 6.5 57.14 21.43 21.43 40 53.3 6.7 23.4 8.5 46.8 21.3 Lowest % 46.2 0 20.5 18.75 18.75 50 12.5 Intermediate, % 35.9 4.8 59.0 27.6 3.4 41.4 27.6 Highest, 2.6 88.1 10.3 Moreover, 6 months after treatment, scarring might be observed on T2-weighted images (19.6%). There was a strong consensus that mpMRI findings could be an indication for biopsies in the follow-up of focal therapy. Targeted biopsy was the best strategy to perform biopsies and 70% of panelists indicated that TRUS-MRI fusion was the best way to guide the targeted biopsies in the follow-up of focal therapy. Recommendations of the Panel • mpMRI was the recommended diagnostic tool for treatment planning in focal therapy for prostate cancer. The panel stated that ideally, this mpMRI should be made on a 3-Tesla device. When a 1.5-Tesla device was the only device available, an endorectal coil was deemed to be essential. A minimum of the following sequences should be included: T1-weighted, T2-weighted and DCE imaging and DWI. The location of the tumour within the prostate could influence the accuracy of the mpMRI, which the clinician should keep in mind. • Magnetic resonance thermometry was regarded as a possible technology for real-time monitoring of thermal ablation. The panel preferred this technology. TRUS-MRI fusion was recommended by the panel for targeting biopsies. Standardized protocols for the acquisition and reporting of mpMRIs were considered of paramount importance and © 2013 The Authors BJU International © 2013 BJU International 703 Muller et al. Table 4 Results regarding treatment guidance. Which imaging technique is used in your hospital for focal therapy guidance, during treatment? TRUS MRI MRI-TRUS fusion We don’t do focal therapy Is there a MRI technique suitable for real-time focal treatment monitoring? Yes No I don’t know If there is a possibility for real-time magnetic resonance focal treatment monitoring, which one do you prefer? Magnetic resonance thermometry TRUS-MRI fusion No preference I do not believe that there is a MRI technique suitable for real-time monitoring Do you recommend the use of TRUS-MRI fusion for use in focal therapy for prostate carcinoma? (Multiple answers possible) Yes, TRUS-MRI fusion for treatment planning Yes, TRUS-MRI fusion for real-time treatment guidance Yes, TRUS-MRI fusion for targeted biopsy No What is your opinion about deformation artifacts in TRUS-MRI fusion? Existent, but always acceptable Only acceptable when data are elastically fused (software correction for tissue deformation) Only acceptable for lesions in the peripheral zone Not acceptable I don’t know Do you think it is important that standardized protocols are used for reporting of prostate MRIs? Yes No Do you use a standardized acquisition/reporting protocol for prostate mpMRIs in your hospital? Yes, ESUR/PI-RADS Guidelines Yes, Likert Score Yes, self developed protocol No I don’t know Do you consider it important that all prostate mpMRIs are made and reported by a specialized radiologist? Yes No How many prostate mpMRIs should a radiologist report on a yearly basis to remain experienced? >30 >50 >75 >100 I don’t know Overall, % Radiologists, % Urologists, % 59.5 35.7 26.2 7.1 35.71 50 14.29 14.29 66.7 36.7 23.3 0 89.4 6.4 4.3 93.75 0 6.25 86.2 10.3 3.4 85.1 12.8 4.3 4.3 87.5 12.5 6.25 0 82.8 10.3 3.4 6.9 42.6 40.4 85.1 10.6 43.75 31.25 87.5 6.25 41.4 44.8 82.8 13.8 8.5 72.3 2.1 2.1 17 12.5 75 0 0 18.75 3.4 72.4 3.4 3.4 17.2 100 0 34 4.8 40.5 7.1 11.9 100 0 0 55.3 12.8 27.7 4.3 100 0 42.68 7.14 50 0 0 100 0 0 56.25 25 18.75 0 100 0 30.77 3.8 34.6 11.5 19.2 100 0 0 55.2 6.9 31 6.9 ESUR/PI-RADS, European Society of Urogenital Radiology/Prostate Imaging – Reporting and Data System. should be used. Furthermore, a specialized and experienced radiologist should report all mpMRI results. • mpMRI was concluded to be the best suitable technology for follow-up after focal therapy and should therefore be used in the follow-up schedule of focal therapy. Immediately after treatment, a successful ablation was defined as a loss of enhancement in the DCE sequence. Targeted biopsies should be carried out if follow-up MRI indicated suspected recurrent/residual tumour. • No consensus could be reached on the topic of template saturation biopsies for patient selection. Forty-six percent of the panel stated that mpMRI was not yet an adequate alternative for template saturation biopsies. 704 © 2013 The Authors BJU International © 2013 BJU International Discussion The use of the Delphi method produced consensus in 41% of the key items (14 out of 34). On some questions there was a considerable difference in opinions between radiologists and urologists (Tables 2–4). Although the panel reached a consensus for 3 Tesla as the ideal field strength in prostate mpMRI, some panelists mentioned that 1.5 Tesla might have the same diagnostic accuracy. This is supported by a recent publication by Bratan et al. [22]. The panel agreed that, with increasing Gleason score, smaller tumours could be detected on mpMRI. Substantiation of this topic was provided in studies by Bratan et al. [22] and Turkbey et al. [23]. As a tool for the real-time guidance of thermal focal therapy, magnetic Multiparametric MRI in focal therapy for prostate cancer Table 5 Results regarding treatment follow-up. Which technique(s) do you recommend for focal therapy follow-up? (Multiple options are possible) mpMRI TRUS Prostate biopsies MRI-TRUS fusion Contrast enhanced ultrasonography PSA DRE Is mpMRI a reliable tool for follow-up after focal therapy for prostate carcinoma? Yes No I don’t know After focal therapy of prostate cancer, when should the first follow-up mpMRI be done? 0–7 days after treatment (baseline) 3 months after treatment 6 months after treatment 1 years after treatment I don’t know At which intervals should mpMRI be performed in the follow-up of focal therapy of prostate cancer? mpMRI every 6 months mpMRI every year no routine mpMRI, only based on clinical indications Immediately after treatment, how does definitive tissue destruction present on a prostate mpMRI? (Multiple answers possible) Low signal on T2-weighted images (scar) Loss of enhancement on DCE-MRI ADC above a certain threshold (dependent on b-value of the scanner) Increased choline/citrate ratio on MRSI Other I don’t know 6 months after treatment, how does definitive tissue destruction present on a prostate mpMRI? (Multiple answers possible) Low signal on T2-weighted images (scar) Loss of enhancement on DCE-MRI ADC above a certain threshold (dependent on b-value of the scanner) Increased choline/citrate ratio on MRSI Other I don’t know Which is the best biopsy strategy for follow-up biopsies after focal therapy? Systematic biopsies Targeted biopsies Template saturation biopsies How should biopsies in the follow-up of focal therapy be guided? TRUS-guided based on mpMRI images MRI-guided Either TRUS- or MRI-guided TRUS-MRI fusion-guided Overall, % Radiologists, % Urologists, % 95.7 8.5 48.9 31.9 8.5 51.1 19.1 100 0 31.25 18.75 0 43.75 12.75 93.1 13.8 58.6 34.5 10.3 55.2 24.1 76.6 17 6.4 81.25 12.5 6.25 72.4 20.7 6.9 17 14.9 63.8 2.1 2.1 12.5 12.5 68.75 0 6.25 17.2 17.2 62.1 3.4 0 51.1 42.6 6.4 68.75 25 6.25 37.9 55.2 6.9 10.6 89.4 4.3 0 4.3 6.4 18.75 100 6.25 6.25 6.25 6.9 82.8 0 0 3.4 6.9 19.6 67.4 2.20 0 6.5 4.3 18.75 68.75 0 0 6.25 6.25 21.4 64.3 3.6 0 7.1 3.6 15.2 82.6 2.2 6.25 93.75 0 21.4 75 3.6 17 4.3 8.5 70.2 18.75 6.25 12.5 62.5 17.2 3.4 6.9 72.4 ADC, apparent diffusion coefficient. resonance thermometry is a suitable technology. Although not widely implemented, magnetic resonance thermometry results seem promising for future application [24]. Furthermore, the panel agreed that TRUS-MRI fusion is a promising technology for targeted biopsies of the prostate. Deformation errors can arise, but these are minimal and therefore acceptable. TRUS-MRI-fusion-guided biopsies have shown similar results to those of MRI-guided biopsies [25]. In the follow-up section, the panel agreed that PSA should be part of the follow-up after focal therapy, but the literature has not yet determined, nor has a consensus been reached on, how to interpret PSA kinetics after focal therapy. Face-to-face consensus methods or expert group discussions are prone to biases. Dominant personalities are known to be capable of influencing the opinion of the group to a significant extent [26]. The Delphi method is very well suited to reduce this type of bias. All panelists were given the opportunity to actively contribute and share their opinions anonymously. During the face-to-face meeting, conclusions were only formulated from the anonymously acquired data; no new input was given. The Delphi method also implies that the group is presented with questions, which are formulated based upon the latest literature, resulting in a high level of validity. Based on their knowledge, the panelists were given the © 2013 The Authors BJU International © 2013 BJU International 705 Muller et al. opportunity to add discussion points, questions and amendments to the series of questions, to achieve consensus about what is important in the view of the group as a whole. Because panelists from Europe, North America, Asia and Australia were participating in the panel, all topics were viewed within this broad perspective. The panel reached a consensus at a unanimity level of ∼80%. This may be considered a limitation, since experts were selected on the basis of their expertise in prostate cancer. For focal therapy of prostate cancer, state-of-the-art imaging is of utmost importance. The physician should be able to target the tumour and has to ensure that, outside the targeted area, no other significant tumour is missed. Through incorporation of the recommendations reported in the present paper, the conduct, interpretation and reporting of mpMRI in treatment planning, treatment guidance and treatment follow-up of focal therapy will be more consistent and standardized. With pooled analyses, the clinical diagnostic accuracy of mpMRI will increase. The panel concluded that mpMRI for treatment planning should ideally be carried out before biopsy; however, limitations such as costs, lack of availability of MRI, lack of standardization and reproducibility, mean that this approach cannot always be applied in daily practice. Previous studies have also recommended such an approach [27]. Imaging criteria for mpMRI are stricter in tissue-preserving strategies such as active surveillance and focal therapy. For focal therapy, it is not only important to be able to see the target lesion, but also to exclude significant tumours elsewhere in the prostate. If the accuracy of mpMRI is great enough to exclude significant tumour sufficiently, template saturation mapping biopsies in patients undergoing focal therapy can potentially be avoided in the future. Additionally, the detection and localization components of mpMRI could assist in targeting biopsies. A large metaanalysis recently published by Nelson et al. [28] showed that MRI-guided biopsies potentially have a detection rate equivalent to transperineal template saturation biopsies; however, these findings are yet to be validated in prospective studies. TRUS-mpMRI fusion can fulfill a significant role in this respect and was also recommended by the panel. It is important to note that most of the literature is generated in high-volume expert centres. Consequently, panel members were also from these centres. It might therefore be challenging to extrapolate these results to settings outside of these expert centres. The relatively low amount of consensus (41% of the topics) indicates that there are many uncertainties in the field. The results of the consensus project are, therefore, not immediately to be used as guidelines for clinical practice. Nevertheless, given the numerous studies that have been performed in this area of research, we anticipate that these consensus statements will be meaningful and that other research groups will 706 © 2013 The Authors BJU International © 2013 BJU International implement the recommendations in new study protocols on focal therapy and imaging. Dickinson et al. [16] already pointed out in 2011 that transperineal saturation biopsies are the optimum reference standard for studies on the diagnostic accuracy of mpMRI, because they overcome random and systematic sampling errors by sampling the gland every 5 mm, provide three-dimensional coordinates for correlation to imaging and can be applied to all men. It is anticipated that future studies, comparing mpMRI with transperineal saturation mapping biopsies, will confirm the important role of mpMRI in a variety of purposes in focal therapy for prostate cancer. In conclusion, focal therapy is an emerging technique for prostate cancer treatment. For this treatment optimum imaging is paramount and mpMRI has the potential to meet these strict imaging requirements. Through a structured consensus method, our panel agreed on several key issues regarding mpMRI for use in focal therapy. 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PloS One 2013; 8: e57480 Correspondence: Berrend Muller, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. e-mail: [email protected] Abbreviations: mpMRI, multiparametric MRI; DCE, dynamic contrast-enhanced; DWI, diffusion-weighted imaging; MRSI, magnetic resonance spectroscopic imaging. © 2013 The Authors BJU International © 2013 BJU International 707