REVIEW URRENT C OPINION
In-bore MRI interventions: current status and future applications Sangeet Ghai a and John Trachtenberg b
Purpose of review This review discusses the feasibility, recent advances and current status of in-bore MRI-guided interventional techniques for diagnosis and treatment of focal prostate cancer (PCa) and also explores the future applications, highlighting the emerging strategies for the treatment of PCa. Recent findings Multiparametric MRI has opened up opportunities for diagnosis and targeted therapeutics to the site of disease within the organ wherein minimizing the incidence of treatment-related toxicity of whole gland therapy. MRI-guided targeted biopsy has a higher detection rate for significant cancer and lower rate of detection of insignificant cancer. In comparison to ultrasound-guided focal therapy, in-bore treatment provides the advantage of real time thermal monitoring during treatment and assessment of treatment coverage by an enhanced scan immediately post-treatment. Preliminary results of ongoing phase I and II in-bore focal PCa treatment trials via transperineal, transrectal and transurethral routes, using different energy modalities for the ablation, have shown promising results. Summary Advances in multiparametric-MRI has opened up opportunities for in-bore targeted focal treatment of PCa in the correctly selected patient. Keywords focal therapy, MRI-guided prostate intervention, prostate cancer, targeted prostate biopsy
INTRODUCTION Prostate cancer (PCa) remains the most commonly diagnosed solid tumor among North American men with 233,000 new PCas estimated to be diagnosed in the USA in 2014 [1]. This is primarily because of widespread use of prostate-specific antigen (PSA) screening and increased biopsies. Routine PSA testing has resulted in a dramatic increase in PCa incidence and stage migration towards organ confined early disease [2]. Multiparametric MRI (mp-MRI) of the prostate has been extensively investigated in recent years [3–6]. It has a high sensitivity, particularly in detecting and localizing clinically significant carcinomas [7,8]. Using its localizing strength, mp-MRI of the prostate has increased opportunities for imageguided diagnosis and treatment strategies [9–14]. When used in conjunction with PSA, mp-MRI followed by targeted biopsy of the MRI visible lesion is now accepted as a better alternative to systematic transrectal ultrasound (TRUS) biopsy [15 ,16,17]. mp-MRI has also opened up opportunities for focal treatment of PCa. New focal therapy techniques aim &
to selectively ablate locally confined, clinically significant index lesions wherein sparing the majority of the prostate gland including the adjacent sensitive structures [18,19]. The index lesion is often visualized on mp-MRI, and therefore targeted for ablation. In-bore visualization of tumor enables accurate targeting, and the advantage of magnetic resonance (MR) thermometry, which provides real time temperature feedback to ensure selective and adequate tumor ablation as well as monitored preservation of sensitive surrounding structures.
a Joint Department of Medical Imaging, University Health Network, University of Toronto and bDepartment of Surgery, Division of Urology, Princess Margaret Hospital, University Health Network, University of Toronto, Ontario, Canada
Correspondence to Dr Sangeet Ghai, MD, FRCR, Assistant Professor, Joint Department of Medical Imaging, Toronto General Hospital, 585 University Avenue, 1 PMB – 283, Toronto, ON, Canada M5G 2N2. Tel: +1 416 340 4800 x3372/3385; fax: +1 416 593 0502; e-mail: [email protected] Curr Opin Urol 2015, 25:205–211 DOI:10.1097/MOU.0000000000000160
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Focal therapy of prostate cancer
KEY POINTS
PCa and had a higher detection rate for significant cancer and lower rate of detection of insignificant cancer [28 ]. Though most reported transrectal prostate needle guidance devices have been in the prone position, Schwab et al. [29] reported successful in-bore biopsy on 50 patients preformed in 70 cm wide-bore 1.5 and 3 T magnets in the more comfortable supine lithotomy position. T2-weighted turbo spin echo, T1-weighted spoiled gradient echo, ultrafast gradient echo and T2-weighted true fast imaging with steady-state precession sequences (bSSFP) have been cited in the studies allowing for good visualization of the needle during the procedure. Menard et al. [30 ] recently reported on in-bore transperineal prostate biopsy for planning of local salvage after radiation therapy. They obtained six cores from the MR suspicious lesions immediately after the diagnostic mp-MRI scan. Diagnostic accuracy of mp-MRI improved by 16% (in three of 19 patients) when a 5 mm margin was added to the tumor target volumes drawn by two readers. This topic is of much interest to physicians who are currently exploring focal PCa therapy. Langer et al. [4] reported that the percentages of individual histologic components in the gland (nuclei, cytoplasm, stroma and lumen space) significantly affect quantitative MRI findings. Thus, ‘sparse’ tumor may be present at the periphery of the MRI visible ‘dense’ portion of the tumor. Therefore, accurate delineation of tumor boundary by biopsy is important for success of focal treatment of PCa, especially when in-bore targeted ablation is being considered. The median reported procedure time in the literature for MR-guided biopsy varies from 30 to 96 min [25,31], which are substantially longer than those reported for TRUS biopsy. Much of this increased time is from repeatedly moving the patient out of the scanner to enable access to the needle, followed by repeat imaging. Some investigators have therefore looked at MR compatible robotic devices via rectal [32], gluteal [33] and perineal approaches [31,34 ,35,36]. Cepek et al. [34 ,35,36] recently described an MR compatible mechatronic system for transperineal needle guidance (Fig. 1). They reported needle delivery time to the target of 9 min. Tilak et al. [31] compared robotic and manual needle guidance templates for in-bore transperineal biopsy in 99 cases and concluded that in the robotic group, the procedure time was shorter, mean accuracy of best needle placement was higher and the cancer volume in samples was also higher. This brings into question the cost-effectiveness of MR-guided in-bore prostate biopsy. de Rooij et al. [37] compared the quality of life and healthcare costs for TRUS-guided biopsy strategy versus the MR-guided imaging based biopsy &
Advances in mp-MRI have opened up opportunities for prostate diagnosis and treatment. In-bore therapy of focal PCa allows for targeted ablation wherein sparing the majority of the prostate gland including the adjacent sensitive structure. Spatial resolution of MRI and MRI thermal feedback during treatment are additional benefits of performing the treatment safely in the magnet (in-bore) with minimal adverse effects. MR-guided FLA is precise, accurate, with few anticipated complications and relatively low cost of the integrated system. MR-guided focused ultrasound and cryoablation are the other new promising techniques for thermal therapy of focal PCa.
Contrast-enhanced scan at the end of procedure outlines the treated nonperfused volume to confirm treatment coverage before taking the patient off the table. A thin (approximately 2 mm) rim of hyperemia or hemostasis from supraphysiological hyperthermia (between 42 and 60 8C) may be seen around the area of necrosis on immediate postablation contrast-enhanced scan, but will eventually develop coagulative necrosis 2–5 days after treatment [20,21]. This article reviews the recent advances and current status of in-bore MRI-guided interventional techniques for diagnosis and treatment of prostate and explores the future possibilities of in-bore MRIguided treatment of PCa. Various ongoing phase I and II in-bore focal PCa treatment trials via transperineal, transrectal and transurethral routes, and using different energy modalities for the ablation, are discussed in the review.
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IN-BORE PROSTATE BIOPSY The first reports of in-bore MRI-guided prostate biopsy were reported in 2000 via a transperineal route using an open configuration 0.5 T strength magnet [22,23]. Open-bore MRI configuration provides easier patient access, but is limited by its low signal-to-noise ratio. Since then, several studies have reported clinical trials within closed-bore magnets (1.5 and 3 T), most using the transrectal approach with the patient in the prone position [17,24–26]. The reported cancer detection rates in these studies range from 8 to 70% [25,27]. In a recent metaanalysis of 16 studies, the authors concluded that MRI-guided targeted biopsy benefits the diagnosis of 206
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FIGURE 1. Diagrammatic representation of the MRI compatible mechatronic device used for transperineal needle insertion and guidance for magnetic resonance-guided focal laser ablation (MRgFLA). Reproduced with permission from [34 ]. &
strategy, modeled to a period of 10 years following initial referral for biopsy. Their results suggested comparable healthcare costs in the two strategies but an improved quality of life in the imaging arm. This benefit is derived from a decrease in men who are overdiagnosed and overtreated as a result of imaging prior to biopsy. mp-MRI provides for improved sampling efficiency, decrease in histopathology costs, fewer missed clinically significant cancers and better characterization of tumor grade [38]. MRI-TRUS fusion biopsy is less expensive than MR-guided in-bore biopsy and can also be performed in a shorter time. Recent results of MRI-TRUS fusion biopsy using different software platforms have shown promising results [39–44] and this technique is therefore likely to provide an alternative targeted biopsy method to overcome the costs of in-bore prostate, but still utilize the advantage of tumor localization on mp-MRI.
MAGNETIC RESONANCE-GUIDED FOCAL LASER ABLATION In-bore MR-guided focal laser ablation (MRgFLA) is currently being evaluated as an energy modality for focal therapy of PCa. FLA utilizes high-energy laser light to generate coagulation through rapid heating. The tissue destruction effect depends upon the amount of energy delivered and on the wavelength of the laser fiber, which regulates the depth of light distribution. Optical fibers for light delivery are from 300 to 600 mm in diameter with the cylindrical diffuser tip varying from 10 to 40 mm in length [45]. Laser is MRI compatible and has distinct advantages over other sources of in-bore thermal energy. As it is an interstitial form of treatment, there are no registration issues which may occur with other sources of
energy such as high-intensity focused ultrasound. Laser ablation is predictable and precise as has been shown in some preclinical and phase I clinical studies, and the intensity of the energy can be dynamically modulated by the operator in real time triggered by MR thermography feedback at the time of treatment. Low cost of the integrated system is another advantage. It allows for targeted ablation (instead of hemiablation or zonal ablation) and therefore is ideally suited for in-bore focal therapy of PCa. At the same time, it is important that the target is clearly visible on the pretreatment MRI and that the laser treatment not only be based on biopsy findings. The procedure is performed as day surgery under deep sedation in the MRI suite after placement of Foleys catheter with the patient in the supine position. T2-weighted turbo spin echo, T1-weighted spoiled gradient echo, ultrafast gradient echo and bSSFP sequences have been used for visualization of the needle during the procedure. Our group has previously reported on contrast agent concentration for filling up the catheter for visualization on spoiled gradient echo sequences [46]. Real-time thermal maps can be obtained using the proton resonance frequency shift, which is based on gradient echoes with long TE (Echo Time) (ideally equal to T2 of the tissue). Three-dimensional processing allows visualization of the thermal map in relation to important surrounding structures. Preclinical trials using 980 nm diode laser (Visualase, Houston, Texas) as a thermal energy source for in-bore focal ablation have shown precise, accurate and predictable ablation zones [20,47,48]. Two separate phase I trials using the transperineal approach, on a cohort of 38 patients [49] and nine patients [50], respectively, have demonstrated its feasibility in humans with minimal or no sideeffects of the treatment. Both studies showed successful ablation at treatment site in approximately 75%, and most of the patients with residual disease had low risk disease, not visible on mp-MRI at 4–6 months post-treatment. Ongoing phase II clinical trial results at our institute (University of Toronto) and University of Chicago are due in 2015. Investigators at University of Toronto are presently using an MR compatible mechatronic device for needle guidance [34 ,35,36,51]. They evaluated 37 consecutive transperineal needle insertions using the mechatronic device in the course of 10 FLA treatments and reported that the median needle guidance error was 3.5 mm and needle delivery time was 9 min [34 ]. Woodrum et al. [52] reported successful in-bore ablation of a 2.2 cm focus of recurrent tumor in the prostatectomy bed using interstitial laser via the transperineal route. Other sites have
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also reported initial success with in-bore focal laser thermal therapy using a transrectal approach [53]. Though these initial results are promising, larger series with follow-up for over 5 years will be needed for validation.
MAGNETIC RESONANCE-GUIDED FOCUSED ULTRASOUND THERAPY Focused ultrasound is a noninvasive method of tissue ablation in which the mechanical energy of sonication is converted to thermal energy, resulting in raised temperature and tissue coagulation [54]. It can be directed with mp-MRI for accurate tumor targeting and monitored in real time with MRI thermography. There are two MR-guided highintensity focused ultrasound approaches, transrectal and transurethral, being tried out in phase I clinical trials at different sites.
TRANSRECTAL MR-GUIDED FOCUSED ULTRASOUND THERAPY The ExAblate 2100 Prostate (Insightec Inc., Haifa, Israel) is a transrectal MR-guided focused ultrasound (MRgFUS) system. The system delivers energy from an endorectal ultrasound transducer filled with degassed 14 8C water to cool the rectum. The transducer is made of about 1000 elements and can steer the ultrasound beam to the desired location in the prostate (Fig. 2). Proof-of-principle study demonstrating coagulative necrosis with no residual tumor in the ablated area was published in 2013 [55]. Our group initially reported the feasibility of transrectal MRgFUS treatment for PCa [56], and have recently reported the results on the first four patients treated with MRgFUS system at our institution in an ongoing phase I trial [57 ]. All six treated ablation zones in the four patients were clear on MRI, and &
five of the six target lesions (83%) were free of disease on follow-up biopsy. The median treated volume was 3.55 cubic centimeters and the median MRI time was 215 min. There was no significant difference in the pretreatment and post-treatment International Index of Erectile Function (IIEF)-15 and International Prostate Symptom Score (IPSS) scores. A recent preclinical study also evaluated the Exablate 2100 Prostate system for targeted continuous volumetric hyperthermia (40–45 8C) with the intention for targeted hyperthermia in conjunction with radiotherapy and chemotherapy [58].
MAGNETIC RESONANCE-GUIDED TRANSURETHRAL FOCUSED ULTRASOUND THERAPY The transurethral device (PAD – 105, Profound Medical Inc., Toronto, Canada) includes a transurethral ultrasound heating applicator and a rotational positioning system, which enables rotation of the ultrasound transducer over a defined angular sector to treat a large volume of the gland. The device is inserted into urethra over a guidewire and positioned in the prostatic urethra for the treatment. The procedure is performed under spinal or general anesthesia after insertion of a suprapubic catheter for continuous drainage of the urinary bladder. Chopra et al. [59] reported the first proof-of-principle study demonstrating its safety and feasibility in eight patients for localized PCa. The treatment volume in this study was a 1808 sector of the posterior gland. Results of the ongoing phase I multicenter trial to evaluate MR-guided transurethral whole gland ablation are expected in 2015. Preliminary results show it to be well tolerated, feasible and a promising technique with low side-effect profile [60].
MAGNETIC RESONANCE-GUIDED FOCAL CRYOABLATION
FIGURE 2. Endorectal focused ultrasound probe featuring the 990-element transducer with continuous circulating degassed cold (14 8C) water. 208
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Onik et al. [61] first described transrectal ultrasoundguided percutaneous prostate cryoablation. A major drawback of performing cryoablation under ultrasound guidance is the poor visualization of the circumferential ablation because of the shadowing artifact from the posterior margin of the ice ball, thereby increasing the potential for complications from the procedure. In-bore MRI-guided focal cryoablation is a new and upcoming technique for focal PCa treatment, which allows real time confirmation of iceball growth with the additional benefit of the spatial resolution provided by MRI to identify the important adjacent structures. Iceball growth can Volume 25 Number 3 May 2015
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In-bore MRI interventions Ghai and Trachtenberg
be monitored in near real time with T1 weighted gradient echo imaging [62]. Overduin et al. [63] reported that a hyperintense rim is seen progressing at the margins caused by shortening of T1 and seen in cooled (less than 20 8C) but as yet nonfreezed margin. MR thermography information is less accurate from cooling tissue and is therefore not routinely used. Also susceptibility artifacts from iceball–normal tissue interface hinders thermal mapping. T2WBLADE (T2 weighted spin echo) sequence, with its reduced sensitivity to movement, has also been used to monitor the iceball growth [64]. Three recent studies have looked at the feasibility of MR-guided cryoablation [62,64,65]. Gangi et al. [64] assessed whole gland cryoablation in 11 patients contraindicated for surgery, eight with newly diagnosed PCa and three with local recurrence following radiation therapy. They placed between four to seven MR compatible cryoprobes (dependent upon prostate volume) transperineally under MRI guidance. Urethral and rectal warmers were used in most of the treatments. The procedure time was between 2 and 4.5 h and the mean hospital stay was 5 days. The treatment was technically successful in 10 of 11 patients. One of the initial patients in the study, in whom the rectal warmer was not used, developed a rectourethral fistula which healed in 3 months. In another study, Woodrum et al. [65] treated 18 patients with local recurrence after radical prostatectomy (six patients also had salvage radiation therapy and subsequent recurrence) in a 1.5-T wide-bore MR magnet. They reported better oncologic results in the group who were treated more aggressively with three freeze– thaw cycles, but at the same time worsening incontinence was reported in three of the nine patients treated aggressively. Bomers et al. [62] evaluated focal cryoablation for recurrent PCa after radiation therapy, ablating only the lesion with margins. The median focal tumor size in the 10 patients was 20 mm and the treatment time was 210.5 min, very similar to the scanner time in our own initial study with transrectal MRgFUS. All patients were discharged 1–2 days following treatment. At 12 months, three patients had recurrent/residual disease at margin of the treated area and were retreated. Urinary stricture was noted in one patient following treatment.
brachytherapy were published in 2000 [66]. The same group of investigators more recently reported results of MRI-guided partial prostate brachytherapy in 318 patients, wherein 125I seeds were placed only in the peripheral zone of the prostate in a 0.5 T MRI unit [67]. They reported PSA free survival rates at 5 and 8 years of 73 and 66.4%, respectively, for intermediate risk cancer and concluded that this technique may not be adequate at this time for intermediate risk disease. High-dose rate brachytherapy under MRI guidance has also been studied by other investigators [66,68,69] and is a useful technique for dose escalation when combined with external beam radiation [70] in an attempt to decrease toxicity from the treatment. Ares et al. [69] applied this technique under MRI guidance and reported encouraging preliminary biochemical disease-free survival.
MAGNETIC RESONANCE-GUIDED BRACHYTHERAPY
Financial support and sponsorship None.
Advances in mp-MRI have opened up the potential to identify index lesions to allow for dose modulation reflecting the differential risk of recurrence. Early results of MRI-guided low-dose rate
Conflicts of interest Both authors are Co-Principal Investigators for the focal MRgFUS and MRgFLA programs at their institute.
CONCLUSION Advantage of localization strength of mp-MRI, MR thermometry and the spatial resolution provided by MRI, makes in-bore MR-guided prostatic interventions ideally suited for targeted diagnosis and treatment. Although MRgFLA has the advantage of being precise, interstitial, with few anticipated complications, MRgFUS could also be combined with local drug delivery for focal therapy of PCa in the future. However, published data on in-bore prostate interventions are limited and larger phase II multicenter trial results are awaited. Although in-bore treatment provides for targeted and accurate ablation, the increased costs associated with MR-guided intervention remains a deterrent. It is important that the procedure times be brought down consistently to under 3 h for its wider application. Use of MRI compatible robots can help to speed up the process. Also, new systems with wider bores would make it easier in the future for the physicians to operate in the magnet. Though MRITRUS fusion is likely to provide a cheaper costeffective alternative to prostate biopsy, ultrasound lacks the spatial resolution and MR thermal feedback advantages of MRI, which are essential for targeted therapy. Acknowledgements None.
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In-bore MRI interventions Ghai and Trachtenberg 51. Cepek J, Lindner U, Davidson SR, et al. Treatment planning for prostate focal laser ablation in the face of needle placement uncertainty. Med Phys 2014; 41:013301. 52. Woodrum DA, Mynderse LA, Gorny KR, et al. 3.0T MR-guided laser ablation of a prostate cancer recurrence in the postsurgical prostate bed. J Vasc Interv Radiol 2011; 22:929–934. 53. Lee T, Mendhiratta N, Sperling D, Lepor H. Focal laser ablation for localized prostate cancer: principles, clinical trials, and our initial experience. Rev Urol 2014; 16:55–66. 54. Hynynen K, McDannold N. MRI guided and monitored focused ultrasound thermal ablation methods: a review of progress. Int J Hyperthermia 2004; 20:725–737. 55. Napoli A, Anzidei M, De Nunzio C, et al. Real-time magnetic resonance-guided high-intensity focused ultrasound focal therapy for localised prostate cancer: preliminary experience. Eur Urol 2013; 63:395–398. 56. Lindner U, Ghai S, Spensieri P, et al. Focal magnetic resonance guided focused ultrasound for prostate cancer: initial North American experience. Can Urol Assoc J ¼ Journal de l’Association des urologues du Canada 2012; 6:E283–E286. 57. Ghai S, Louis AS, Van Vliet M, et al. Real time magnetic resonance guided & focused ultrasound for focal therapy of locally confined low risk prostate cancer: feasibility and preliminary outcomes. Am J Roentgenol 2015. (in press). This phase I clinical trial demonstrates the safety and feasibiloty of MRI-guided focused ultrasound ablation for low risk PCa. 58. Salgaonkar VA, Prakash P, Rieke V, et al. Model-based feasibility assessment and evaluation of prostate hyperthermia with a commercial MR-guided endorectal HIFU ablation array. Med Phys 2014; 41:033301. 59. Chopra R, Colquhoun A, Burtnyk M, et al. MR imaging-controlled transurethral ultrasound therapy for conformal treatment of prostate tissue: initial feasibility in humans. Radiology 2012; 265:303–313. 60. Billia M, Burtnyk M, Kuru T, et al. 1133 MRI-guided transurethral ultrasound ablation of prostate cancer: Preliminary outcomes of a phase I clinical trial. Eur Urol Suppl 2014; 13:e1133.
61. Onik GM, Cohen JK, Reyes GD, et al. Transrectal ultrasound-guided percutaneous radical cryosurgical ablation of the prostate. Cancer 1993; 15:1993; 72:1291–1299. 62. Bomers JG, Yakar D, Overduin CG, et al. MR imaging-guided focal cryoablation in patients with recurrent prostate cancer. Radiology 2013; 268:451– 460. 63. Overduin CG, Bomers JG, Jenniskens SF, et al. T1-weighted MR image contrast around a cryoablation iceball: a phantom study and initial comparison with in vivo findings. Med Phys 2014; 41:112301. 64. Gangi A, Tsoumakidou G, Abdelli O, et al. Percutaneous MR-guided cryoablation of prostate cancer: initial experience. Eur Radiol 2012; 22:1829– 1835. 65. Woodrum DA, Kawashima A, Karnes RJ, et al. Magnetic resonance imagingguided cryoablation of recurrent prostate cancer after radical prostatectomy: initial single institution experience. Urology 2013; 82:870–875. 66. D’Amico A, Cormack R, Kumar S, Tempany CM. Real-time magnetic resonance imaging-guided brachytherapy in the treatment of selected patients with clinically localized prostate cancer. J Endourol/Endourol Soc 2000; 14:367–370. 67. Nguyen PL, Chen MH, Zhang Y, et al. Updated results of magnetic resonance imaging guided partial prostate brachytherapy for favorable risk prostate cancer: implications for focal therapy. J Urol 2012; 188:1151–1156. 68. Menard C, Susil RC, Choyke P, et al. MRI-guided HDR prostate brachytherapy in standard 1.5T scanner. Int J Radiat Oncol Biol Phys 2004; 59:1414– 1423. 69. Ares C, Popowski Y, Pampallona S, et al. Hypofractionated boost with highdose-rate brachytherapy and open magnetic resonance imaging-guided implants for locally aggressive prostate cancer: a sequential dose-escalation pilot study. Int J Radiat Oncol Biol Phys 2009; 75:656–663. 70. Lips IM, van der Heide UA, Haustermans K, et al. Single blind randomized phase III trial to investigate the benefit of a focal lesion ablative microboost in prostate cancer (FLAME-trial): study protocol for a randomized controlled trial. Trials 2011; 12:255.
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In-bore MRI interventions: current status and future applications Sangeet Ghai a and John Trachtenberg b
Purpose of review This review discusses the feasibility, recent advances and current status of in-bore MRI-guided interventional techniques for diagnosis and treatment of focal prostate cancer (PCa) and also explores the future applications, highlighting the emerging strategies for the treatment of PCa. Recent findings Multiparametric MRI has opened up opportunities for diagnosis and targeted therapeutics to the site of disease within the organ wherein minimizing the incidence of treatment-related toxicity of whole gland therapy. MRI-guided targeted biopsy has a higher detection rate for significant cancer and lower rate of detection of insignificant cancer. In comparison to ultrasound-guided focal therapy, in-bore treatment provides the advantage of real time thermal monitoring during treatment and assessment of treatment coverage by an enhanced scan immediately post-treatment. Preliminary results of ongoing phase I and II in-bore focal PCa treatment trials via transperineal, transrectal and transurethral routes, using different energy modalities for the ablation, have shown promising results. Summary Advances in multiparametric-MRI has opened up opportunities for in-bore targeted focal treatment of PCa in the correctly selected patient. Keywords focal therapy, MRI-guided prostate intervention, prostate cancer, targeted prostate biopsy
INTRODUCTION Prostate cancer (PCa) remains the most commonly diagnosed solid tumor among North American men with 233,000 new PCas estimated to be diagnosed in the USA in 2014 [1]. This is primarily because of widespread use of prostate-specific antigen (PSA) screening and increased biopsies. Routine PSA testing has resulted in a dramatic increase in PCa incidence and stage migration towards organ confined early disease [2]. Multiparametric MRI (mp-MRI) of the prostate has been extensively investigated in recent years [3–6]. It has a high sensitivity, particularly in detecting and localizing clinically significant carcinomas [7,8]. Using its localizing strength, mp-MRI of the prostate has increased opportunities for imageguided diagnosis and treatment strategies [9–14]. When used in conjunction with PSA, mp-MRI followed by targeted biopsy of the MRI visible lesion is now accepted as a better alternative to systematic transrectal ultrasound (TRUS) biopsy [15 ,16,17]. mp-MRI has also opened up opportunities for focal treatment of PCa. New focal therapy techniques aim &
to selectively ablate locally confined, clinically significant index lesions wherein sparing the majority of the prostate gland including the adjacent sensitive structures [18,19]. The index lesion is often visualized on mp-MRI, and therefore targeted for ablation. In-bore visualization of tumor enables accurate targeting, and the advantage of magnetic resonance (MR) thermometry, which provides real time temperature feedback to ensure selective and adequate tumor ablation as well as monitored preservation of sensitive surrounding structures.
a Joint Department of Medical Imaging, University Health Network, University of Toronto and bDepartment of Surgery, Division of Urology, Princess Margaret Hospital, University Health Network, University of Toronto, Ontario, Canada
Correspondence to Dr Sangeet Ghai, MD, FRCR, Assistant Professor, Joint Department of Medical Imaging, Toronto General Hospital, 585 University Avenue, 1 PMB – 283, Toronto, ON, Canada M5G 2N2. Tel: +1 416 340 4800 x3372/3385; fax: +1 416 593 0502; e-mail: [email protected] Curr Opin Urol 2015, 25:205–211 DOI:10.1097/MOU.0000000000000160
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Focal therapy of prostate cancer
KEY POINTS
PCa and had a higher detection rate for significant cancer and lower rate of detection of insignificant cancer [28 ]. Though most reported transrectal prostate needle guidance devices have been in the prone position, Schwab et al. [29] reported successful in-bore biopsy on 50 patients preformed in 70 cm wide-bore 1.5 and 3 T magnets in the more comfortable supine lithotomy position. T2-weighted turbo spin echo, T1-weighted spoiled gradient echo, ultrafast gradient echo and T2-weighted true fast imaging with steady-state precession sequences (bSSFP) have been cited in the studies allowing for good visualization of the needle during the procedure. Menard et al. [30 ] recently reported on in-bore transperineal prostate biopsy for planning of local salvage after radiation therapy. They obtained six cores from the MR suspicious lesions immediately after the diagnostic mp-MRI scan. Diagnostic accuracy of mp-MRI improved by 16% (in three of 19 patients) when a 5 mm margin was added to the tumor target volumes drawn by two readers. This topic is of much interest to physicians who are currently exploring focal PCa therapy. Langer et al. [4] reported that the percentages of individual histologic components in the gland (nuclei, cytoplasm, stroma and lumen space) significantly affect quantitative MRI findings. Thus, ‘sparse’ tumor may be present at the periphery of the MRI visible ‘dense’ portion of the tumor. Therefore, accurate delineation of tumor boundary by biopsy is important for success of focal treatment of PCa, especially when in-bore targeted ablation is being considered. The median reported procedure time in the literature for MR-guided biopsy varies from 30 to 96 min [25,31], which are substantially longer than those reported for TRUS biopsy. Much of this increased time is from repeatedly moving the patient out of the scanner to enable access to the needle, followed by repeat imaging. Some investigators have therefore looked at MR compatible robotic devices via rectal [32], gluteal [33] and perineal approaches [31,34 ,35,36]. Cepek et al. [34 ,35,36] recently described an MR compatible mechatronic system for transperineal needle guidance (Fig. 1). They reported needle delivery time to the target of 9 min. Tilak et al. [31] compared robotic and manual needle guidance templates for in-bore transperineal biopsy in 99 cases and concluded that in the robotic group, the procedure time was shorter, mean accuracy of best needle placement was higher and the cancer volume in samples was also higher. This brings into question the cost-effectiveness of MR-guided in-bore prostate biopsy. de Rooij et al. [37] compared the quality of life and healthcare costs for TRUS-guided biopsy strategy versus the MR-guided imaging based biopsy &
Advances in mp-MRI have opened up opportunities for prostate diagnosis and treatment. In-bore therapy of focal PCa allows for targeted ablation wherein sparing the majority of the prostate gland including the adjacent sensitive structure. Spatial resolution of MRI and MRI thermal feedback during treatment are additional benefits of performing the treatment safely in the magnet (in-bore) with minimal adverse effects. MR-guided FLA is precise, accurate, with few anticipated complications and relatively low cost of the integrated system. MR-guided focused ultrasound and cryoablation are the other new promising techniques for thermal therapy of focal PCa.
Contrast-enhanced scan at the end of procedure outlines the treated nonperfused volume to confirm treatment coverage before taking the patient off the table. A thin (approximately 2 mm) rim of hyperemia or hemostasis from supraphysiological hyperthermia (between 42 and 60 8C) may be seen around the area of necrosis on immediate postablation contrast-enhanced scan, but will eventually develop coagulative necrosis 2–5 days after treatment [20,21]. This article reviews the recent advances and current status of in-bore MRI-guided interventional techniques for diagnosis and treatment of prostate and explores the future possibilities of in-bore MRIguided treatment of PCa. Various ongoing phase I and II in-bore focal PCa treatment trials via transperineal, transrectal and transurethral routes, and using different energy modalities for the ablation, are discussed in the review.
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IN-BORE PROSTATE BIOPSY The first reports of in-bore MRI-guided prostate biopsy were reported in 2000 via a transperineal route using an open configuration 0.5 T strength magnet [22,23]. Open-bore MRI configuration provides easier patient access, but is limited by its low signal-to-noise ratio. Since then, several studies have reported clinical trials within closed-bore magnets (1.5 and 3 T), most using the transrectal approach with the patient in the prone position [17,24–26]. The reported cancer detection rates in these studies range from 8 to 70% [25,27]. In a recent metaanalysis of 16 studies, the authors concluded that MRI-guided targeted biopsy benefits the diagnosis of 206
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In-bore MRI interventions Ghai and Trachtenberg
FIGURE 1. Diagrammatic representation of the MRI compatible mechatronic device used for transperineal needle insertion and guidance for magnetic resonance-guided focal laser ablation (MRgFLA). Reproduced with permission from [34 ]. &
strategy, modeled to a period of 10 years following initial referral for biopsy. Their results suggested comparable healthcare costs in the two strategies but an improved quality of life in the imaging arm. This benefit is derived from a decrease in men who are overdiagnosed and overtreated as a result of imaging prior to biopsy. mp-MRI provides for improved sampling efficiency, decrease in histopathology costs, fewer missed clinically significant cancers and better characterization of tumor grade [38]. MRI-TRUS fusion biopsy is less expensive than MR-guided in-bore biopsy and can also be performed in a shorter time. Recent results of MRI-TRUS fusion biopsy using different software platforms have shown promising results [39–44] and this technique is therefore likely to provide an alternative targeted biopsy method to overcome the costs of in-bore prostate, but still utilize the advantage of tumor localization on mp-MRI.
MAGNETIC RESONANCE-GUIDED FOCAL LASER ABLATION In-bore MR-guided focal laser ablation (MRgFLA) is currently being evaluated as an energy modality for focal therapy of PCa. FLA utilizes high-energy laser light to generate coagulation through rapid heating. The tissue destruction effect depends upon the amount of energy delivered and on the wavelength of the laser fiber, which regulates the depth of light distribution. Optical fibers for light delivery are from 300 to 600 mm in diameter with the cylindrical diffuser tip varying from 10 to 40 mm in length [45]. Laser is MRI compatible and has distinct advantages over other sources of in-bore thermal energy. As it is an interstitial form of treatment, there are no registration issues which may occur with other sources of
energy such as high-intensity focused ultrasound. Laser ablation is predictable and precise as has been shown in some preclinical and phase I clinical studies, and the intensity of the energy can be dynamically modulated by the operator in real time triggered by MR thermography feedback at the time of treatment. Low cost of the integrated system is another advantage. It allows for targeted ablation (instead of hemiablation or zonal ablation) and therefore is ideally suited for in-bore focal therapy of PCa. At the same time, it is important that the target is clearly visible on the pretreatment MRI and that the laser treatment not only be based on biopsy findings. The procedure is performed as day surgery under deep sedation in the MRI suite after placement of Foleys catheter with the patient in the supine position. T2-weighted turbo spin echo, T1-weighted spoiled gradient echo, ultrafast gradient echo and bSSFP sequences have been used for visualization of the needle during the procedure. Our group has previously reported on contrast agent concentration for filling up the catheter for visualization on spoiled gradient echo sequences [46]. Real-time thermal maps can be obtained using the proton resonance frequency shift, which is based on gradient echoes with long TE (Echo Time) (ideally equal to T2 of the tissue). Three-dimensional processing allows visualization of the thermal map in relation to important surrounding structures. Preclinical trials using 980 nm diode laser (Visualase, Houston, Texas) as a thermal energy source for in-bore focal ablation have shown precise, accurate and predictable ablation zones [20,47,48]. Two separate phase I trials using the transperineal approach, on a cohort of 38 patients [49] and nine patients [50], respectively, have demonstrated its feasibility in humans with minimal or no sideeffects of the treatment. Both studies showed successful ablation at treatment site in approximately 75%, and most of the patients with residual disease had low risk disease, not visible on mp-MRI at 4–6 months post-treatment. Ongoing phase II clinical trial results at our institute (University of Toronto) and University of Chicago are due in 2015. Investigators at University of Toronto are presently using an MR compatible mechatronic device for needle guidance [34 ,35,36,51]. They evaluated 37 consecutive transperineal needle insertions using the mechatronic device in the course of 10 FLA treatments and reported that the median needle guidance error was 3.5 mm and needle delivery time was 9 min [34 ]. Woodrum et al. [52] reported successful in-bore ablation of a 2.2 cm focus of recurrent tumor in the prostatectomy bed using interstitial laser via the transperineal route. Other sites have
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also reported initial success with in-bore focal laser thermal therapy using a transrectal approach [53]. Though these initial results are promising, larger series with follow-up for over 5 years will be needed for validation.
MAGNETIC RESONANCE-GUIDED FOCUSED ULTRASOUND THERAPY Focused ultrasound is a noninvasive method of tissue ablation in which the mechanical energy of sonication is converted to thermal energy, resulting in raised temperature and tissue coagulation [54]. It can be directed with mp-MRI for accurate tumor targeting and monitored in real time with MRI thermography. There are two MR-guided highintensity focused ultrasound approaches, transrectal and transurethral, being tried out in phase I clinical trials at different sites.
TRANSRECTAL MR-GUIDED FOCUSED ULTRASOUND THERAPY The ExAblate 2100 Prostate (Insightec Inc., Haifa, Israel) is a transrectal MR-guided focused ultrasound (MRgFUS) system. The system delivers energy from an endorectal ultrasound transducer filled with degassed 14 8C water to cool the rectum. The transducer is made of about 1000 elements and can steer the ultrasound beam to the desired location in the prostate (Fig. 2). Proof-of-principle study demonstrating coagulative necrosis with no residual tumor in the ablated area was published in 2013 [55]. Our group initially reported the feasibility of transrectal MRgFUS treatment for PCa [56], and have recently reported the results on the first four patients treated with MRgFUS system at our institution in an ongoing phase I trial [57 ]. All six treated ablation zones in the four patients were clear on MRI, and &
five of the six target lesions (83%) were free of disease on follow-up biopsy. The median treated volume was 3.55 cubic centimeters and the median MRI time was 215 min. There was no significant difference in the pretreatment and post-treatment International Index of Erectile Function (IIEF)-15 and International Prostate Symptom Score (IPSS) scores. A recent preclinical study also evaluated the Exablate 2100 Prostate system for targeted continuous volumetric hyperthermia (40–45 8C) with the intention for targeted hyperthermia in conjunction with radiotherapy and chemotherapy [58].
MAGNETIC RESONANCE-GUIDED TRANSURETHRAL FOCUSED ULTRASOUND THERAPY The transurethral device (PAD – 105, Profound Medical Inc., Toronto, Canada) includes a transurethral ultrasound heating applicator and a rotational positioning system, which enables rotation of the ultrasound transducer over a defined angular sector to treat a large volume of the gland. The device is inserted into urethra over a guidewire and positioned in the prostatic urethra for the treatment. The procedure is performed under spinal or general anesthesia after insertion of a suprapubic catheter for continuous drainage of the urinary bladder. Chopra et al. [59] reported the first proof-of-principle study demonstrating its safety and feasibility in eight patients for localized PCa. The treatment volume in this study was a 1808 sector of the posterior gland. Results of the ongoing phase I multicenter trial to evaluate MR-guided transurethral whole gland ablation are expected in 2015. Preliminary results show it to be well tolerated, feasible and a promising technique with low side-effect profile [60].
MAGNETIC RESONANCE-GUIDED FOCAL CRYOABLATION
FIGURE 2. Endorectal focused ultrasound probe featuring the 990-element transducer with continuous circulating degassed cold (14 8C) water. 208
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Onik et al. [61] first described transrectal ultrasoundguided percutaneous prostate cryoablation. A major drawback of performing cryoablation under ultrasound guidance is the poor visualization of the circumferential ablation because of the shadowing artifact from the posterior margin of the ice ball, thereby increasing the potential for complications from the procedure. In-bore MRI-guided focal cryoablation is a new and upcoming technique for focal PCa treatment, which allows real time confirmation of iceball growth with the additional benefit of the spatial resolution provided by MRI to identify the important adjacent structures. Iceball growth can Volume 25 Number 3 May 2015
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In-bore MRI interventions Ghai and Trachtenberg
be monitored in near real time with T1 weighted gradient echo imaging [62]. Overduin et al. [63] reported that a hyperintense rim is seen progressing at the margins caused by shortening of T1 and seen in cooled (less than 20 8C) but as yet nonfreezed margin. MR thermography information is less accurate from cooling tissue and is therefore not routinely used. Also susceptibility artifacts from iceball–normal tissue interface hinders thermal mapping. T2WBLADE (T2 weighted spin echo) sequence, with its reduced sensitivity to movement, has also been used to monitor the iceball growth [64]. Three recent studies have looked at the feasibility of MR-guided cryoablation [62,64,65]. Gangi et al. [64] assessed whole gland cryoablation in 11 patients contraindicated for surgery, eight with newly diagnosed PCa and three with local recurrence following radiation therapy. They placed between four to seven MR compatible cryoprobes (dependent upon prostate volume) transperineally under MRI guidance. Urethral and rectal warmers were used in most of the treatments. The procedure time was between 2 and 4.5 h and the mean hospital stay was 5 days. The treatment was technically successful in 10 of 11 patients. One of the initial patients in the study, in whom the rectal warmer was not used, developed a rectourethral fistula which healed in 3 months. In another study, Woodrum et al. [65] treated 18 patients with local recurrence after radical prostatectomy (six patients also had salvage radiation therapy and subsequent recurrence) in a 1.5-T wide-bore MR magnet. They reported better oncologic results in the group who were treated more aggressively with three freeze– thaw cycles, but at the same time worsening incontinence was reported in three of the nine patients treated aggressively. Bomers et al. [62] evaluated focal cryoablation for recurrent PCa after radiation therapy, ablating only the lesion with margins. The median focal tumor size in the 10 patients was 20 mm and the treatment time was 210.5 min, very similar to the scanner time in our own initial study with transrectal MRgFUS. All patients were discharged 1–2 days following treatment. At 12 months, three patients had recurrent/residual disease at margin of the treated area and were retreated. Urinary stricture was noted in one patient following treatment.
brachytherapy were published in 2000 [66]. The same group of investigators more recently reported results of MRI-guided partial prostate brachytherapy in 318 patients, wherein 125I seeds were placed only in the peripheral zone of the prostate in a 0.5 T MRI unit [67]. They reported PSA free survival rates at 5 and 8 years of 73 and 66.4%, respectively, for intermediate risk cancer and concluded that this technique may not be adequate at this time for intermediate risk disease. High-dose rate brachytherapy under MRI guidance has also been studied by other investigators [66,68,69] and is a useful technique for dose escalation when combined with external beam radiation [70] in an attempt to decrease toxicity from the treatment. Ares et al. [69] applied this technique under MRI guidance and reported encouraging preliminary biochemical disease-free survival.
MAGNETIC RESONANCE-GUIDED BRACHYTHERAPY
Financial support and sponsorship None.
Advances in mp-MRI have opened up the potential to identify index lesions to allow for dose modulation reflecting the differential risk of recurrence. Early results of MRI-guided low-dose rate
Conflicts of interest Both authors are Co-Principal Investigators for the focal MRgFUS and MRgFLA programs at their institute.
CONCLUSION Advantage of localization strength of mp-MRI, MR thermometry and the spatial resolution provided by MRI, makes in-bore MR-guided prostatic interventions ideally suited for targeted diagnosis and treatment. Although MRgFLA has the advantage of being precise, interstitial, with few anticipated complications, MRgFUS could also be combined with local drug delivery for focal therapy of PCa in the future. However, published data on in-bore prostate interventions are limited and larger phase II multicenter trial results are awaited. Although in-bore treatment provides for targeted and accurate ablation, the increased costs associated with MR-guided intervention remains a deterrent. It is important that the procedure times be brought down consistently to under 3 h for its wider application. Use of MRI compatible robots can help to speed up the process. Also, new systems with wider bores would make it easier in the future for the physicians to operate in the magnet. Though MRITRUS fusion is likely to provide a cheaper costeffective alternative to prostate biopsy, ultrasound lacks the spatial resolution and MR thermal feedback advantages of MRI, which are essential for targeted therapy. Acknowledgements None.
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Eur Urol 2014. [Epub ahead of print] 42. Logan JK, Rais-Bahrami S, Turkbey B, et al. Current status of magnetic resonance imaging (MRI) and ultrasonography fusion software platforms for guidance of prostate biopsies. BJU Int 2014; 114:641–652. 43. Delongchamps NB, Lefevre A, Bouazza N, et al. Detection of significant prostate cancer with MR-targeted biopsies: should TRUS-MRI fusion guided biopsies alone be a standard of care? J Urol 2014. [Epub ahead of print] 44. Baco E, Ukimura O, Rud E, et al. Magnetic resonance imaging-transectal ultrasound image-fusion biopsies accurately characterize the index tumor: correlation with step-sectioned radical prostatectomy specimens in 135 patients. Eur Urol 2014. [Epub ahead of print] 45. Colin P, Mordon S, Nevoux P, et al. Focal laser ablation of prostate cancer: definition, needs, and future. Adv Urol 2012; 2012:589160. 46. Sussman MS, Lindner U, Haider M, et al. 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In-bore MRI interventions Ghai and Trachtenberg 51. Cepek J, Lindner U, Davidson SR, et al. Treatment planning for prostate focal laser ablation in the face of needle placement uncertainty. Med Phys 2014; 41:013301. 52. Woodrum DA, Mynderse LA, Gorny KR, et al. 3.0T MR-guided laser ablation of a prostate cancer recurrence in the postsurgical prostate bed. J Vasc Interv Radiol 2011; 22:929–934. 53. Lee T, Mendhiratta N, Sperling D, Lepor H. Focal laser ablation for localized prostate cancer: principles, clinical trials, and our initial experience. Rev Urol 2014; 16:55–66. 54. Hynynen K, McDannold N. MRI guided and monitored focused ultrasound thermal ablation methods: a review of progress. Int J Hyperthermia 2004; 20:725–737. 55. Napoli A, Anzidei M, De Nunzio C, et al. Real-time magnetic resonance-guided high-intensity focused ultrasound focal therapy for localised prostate cancer: preliminary experience. Eur Urol 2013; 63:395–398. 56. Lindner U, Ghai S, Spensieri P, et al. Focal magnetic resonance guided focused ultrasound for prostate cancer: initial North American experience. Can Urol Assoc J ¼ Journal de l’Association des urologues du Canada 2012; 6:E283–E286. 57. Ghai S, Louis AS, Van Vliet M, et al. Real time magnetic resonance guided & focused ultrasound for focal therapy of locally confined low risk prostate cancer: feasibility and preliminary outcomes. Am J Roentgenol 2015. (in press). This phase I clinical trial demonstrates the safety and feasibiloty of MRI-guided focused ultrasound ablation for low risk PCa. 58. Salgaonkar VA, Prakash P, Rieke V, et al. Model-based feasibility assessment and evaluation of prostate hyperthermia with a commercial MR-guided endorectal HIFU ablation array. Med Phys 2014; 41:033301. 59. Chopra R, Colquhoun A, Burtnyk M, et al. MR imaging-controlled transurethral ultrasound therapy for conformal treatment of prostate tissue: initial feasibility in humans. Radiology 2012; 265:303–313. 60. Billia M, Burtnyk M, Kuru T, et al. 1133 MRI-guided transurethral ultrasound ablation of prostate cancer: Preliminary outcomes of a phase I clinical trial. Eur Urol Suppl 2014; 13:e1133.
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