Prostate cancer: state of the art imaging and focal treatment

Clinical Radiology xxx (2017) 1e15

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Review

Prostate cancer: state of the art imaging and focal treatment D.A. Woodrum a, *, A. Kawashima a, K.R. Gorny a, L.A. Mynderse b a b

Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA Department of Urology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA

art icl e i nformat ion Article history: Received 14 November 2016 Received in revised form 26 January 2017 Accepted 7 February 2017

In 2016, it is estimated 180,890 men are newly diagnosed with prostate cancer and 3,306,760 men live with prostate cancer in the United States. The introduction of multiparametric (mp) magnetic resonance imaging (MRI) of the prostate, standardised interpretation guidelines such as Prostate Imaging Reporting and Data System (PI-RADS version 2), and MRI-based targeted biopsy has improved detection of clinically significant prostate cancer. Accurate risk stratification (Gleason grade/score and tumour stage) using imaging and image-guided targeted biopsy has become critical for the management of patients with prostate cancer. Recent advances in MRI-guided minimally invasive ablative treatment (MIAT) utilising cryoablation, laser ablation, high-intensity focused ultrasound ablation, have allowed accurate focal or regional delivery of optimal thermal energy to the biopsy proven, MRI-detected tumour, under real-time or near simultaneous MRI monitoring of the ablation zone. A contemporary review on prostate mpMRI, MRI-based targeted biopsy, and MRI-guided ablation techniques is presented. Ó 2017 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.

Introduction The American Cancer Society (ACS) estimates that there are 3,306,760 people living with prostate cancer in the United States and 180,890 new cases of prostate cancer will be diagnosed.1 In 2016 prostate cancer was the most commonly diagnosed non-cutaneous cancer and secondleading cause of death in men.2 With the dramatic increase in good-quality diagnostic multiparametric (mp) magnetic resonance imaging (MRI), organ-confined prostate cancer is increasingly visible, targetable, and potentially treatable with focal ablative technologies.1,3,4

* Guarantor and correspondent: D. A. Woodrum, Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel.: þ1 507-255-8454. E-mail address: [email protected] (D.A. Woodrum).

Unfortunately, the timeline and variability of prostate cancer progression from organ-confined disease to extraprostatic spread is unknown; however, it seems intuitive that early detection and proper characterisation may play a role in preventing the development of metastatic disease.5 In view of the significant disparity on recommendations for early detection and prostate cancer screening among various scientific organisations (American Urological Association, American Society of Clinical Oncology, National Comprehensive Cancer Network, American Cancer Society, US Preventative Task Force and the European Association of Urology), and the uncertainty of the harm versus benefit of screening, this review will not delve into this controversy. Our focus will be on the current state of the art of prostate imaging, biopsy, and ablation techniques. The significance of precise image identification and biopsy is further amplified by level 1 evidence supporting

http://dx.doi.org/10.1016/j.crad.2017.02.010 0009-9260/Ó 2017 Published by Elsevier Ltd on behalf of The Royal College of Radiologists.

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detection and subsequent aggressive treatment of intermediate and high-risk prostate cancer.6 Therefore, accurate ascription of cancer risk (i.e., grade and stage) using imaging and biopsy is critical. Advances in prostate treatment have become integrated with imaging, image identification, and image guided biopsy, and therapy propelling prostate treatment solutions forward faster than ever.

Importance of MRI for prostate imaging Native prostate cancer Prostate cancer has traditionally been diagnosed by prostate-specific antigen (PSA) screening and digital rectal examination (DRE) followed by DRE-directed biopsy. Use of ultrasound imaging has helped direct the biopsies further but has fallen short of being sensitive enough to find all the prostate cancer within the gland. Furthermore, systematic (non-targeted) sampling the entire organ has provided some answers but may also miss or under-sample small volume, but clinically significant disease, which may result in delayed diagnosis and treatment. MRI is the best imaging method of the prostate and periprostatic structures because MRI provides superior softtissue contrast resolution, high spatial resolution, multiplanar imaging capabilities, and a field of view larger than transrectal ultrasound. The use of integrated endorectal and pelvic phased-array coils has led to improved visualisation of the prostatic fossa. T2-weighted imaging (WI) is sensitive in depicting prostate cancer; however, decreased T2 signal intensity is not specific for prostate cancer and can be seen in benign conditions. Functional parametric imaging including dynamic contrast-enhanced imaging (DCEI), diffusion-weighted imaging (DWI), and MRI spectroscopic imaging (MRSI) complement morphological MRI by reflecting perfusion characteristics, Brownian motion of water molecules, and metabolic profiles, respectively. Significant inverse correlation was shown between the apparent diffusion coefficient (ADC) value and Gleason score/highest grade.7 A combination of T2WI, DWI and DCEI with or without MRSI, is referred to as mpMRI. The introduction and maturation of mpMRI now allows for imagingbased identification of prostate cancer, which may improve diagnostic accuracy for higher-risk tumours.8 In 2015, a consensus panel agreed to Prostate ImagingeReporting and Data System (PI-RADS) version 2, which promoted standardised MRI acquisition and interpretation to improve detection, localisation, characterisation, and risk stratification of clinically significant prostate cancer in treatment naive prostate glands.9 Targeted biopsy of suspected cancer lesions detected by MRI is associated with increased detection of high-risk prostate cancer and decreased detection of low-risk prostate cancer particularly with the aid of MRI/ultrasound fusion platforms.10 The use of mpMRI has expanded beyond staging to detection, characterisation, monitoring for active surveillance, and cases of suspected recurrence after failed definitive therapy (Fig 1 aed).

The use of MRI for recurrent prostate cancer continues to evolve and has potential to evaluate both local recurrence and distant bony and nodal metastases.11 In 2013, a consensus panel chaired by Professor Michael Marberger endorsed utilisation mpMRI to identify patients for focal therapy.12 mpMRI is capable of localising small tumours for focal therapy. Although mpMRI plays an established, critical role in native and recurrent prostate cancer imaging, functional, metabolic imaging for prostate cancer is in its formative years. 11C-choline positron-emission tomography (PET)/computed tomography (CT) has an advantage to reveal both local recurrent and distant metastatic prostate cancers. 11C-choline PET/CT had a sensitivity of 73%, a specificity of 88%, a positive predictive value (PPV) of 92%, a negative predictive value (NPV) of 61%, and an accuracy of 78% for the detection of clinically suspected recurrent prostate cancer in postsurgical patients.13 In a study of postprostatectomy patients with rising PSA, mpMRI is superior for the detection of local recurrence, 11C-choline PET/CT is superior for pelvic nodal metastasis, and both are equally excellent for pelvic bone metastasis. 11C-choline PET/CT and mpMRI are complementary for restaging prostatectomy patients with suspected recurrent disease and exhibit diverse patterns of recurrence with implications for optimal salvage treatment strategies.11,14 Furthermore, new readily available PET agents including 68Ga-prostate-specific membrane antigen (PSMA) indicate favourable sensitivity and specificity profiles compared to choline-based PET imaging techniques.15 Additionally, a recent publication demonstrated that late 3 hour imaging of 68Ga-PSMA helped to clarify activity within the prostate due to decreased activity within the bladder at this time point.16 Early work with simultaneous MRI/PET shows promise in capitalising both the functional aspects of PET with the superb anatomical capabilities of MRI.17 With the limitations of ultrasound and PET/CT, MRI remains pre-eminent for the detection and staging of prostate tumours within the pelvis. MRI provides superior softtissue contrast resolution, high spatial resolution, direct multiplanar imaging capabilities, and a large field of view.

Recurrent prostate cancer After a definitive radical prostatectomy, patients are followed at periodic intervals with measurement of serum PSA and DRE; however, DRE is frequently unreliable in evaluating local recurrent disease after radical prostatectomy. Following radical prostatectomy, PSA levels are expected to be undetectable within several weeks of surgery. If there is a rise in a previously undetectable or stable postoperative PSA level (biochemical failure), a prompt search for persistent, recurrent, or metastatic disease should be pursued; however, PSA alone does not differentiate local from distant disease recurrence. There are three main categories of recurrence after radical prostatectomy for prostate cancer: (1) local recurrence in the prostatic bed, (2) distant metastasis (e.g., bone, lymph node), and (3) a combination of local recurrence and distant metastasis. Therefore, the major objective of diagnostic imaging studies

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Figure 1 A 62-year-old man with a history of adenocarcinoma, low-volume Gleason score 3þ3, diagnosed a year earlier, presented with elevated PSA to 9.6 from 4.9 (ng/ml). mpMRI at 3 T with an endorectal coil was performed for further characterisation. (a) Axial and (b) sagittal T2weighted images demonstrate an area of decreased signal intensity in the left anterior prostate at the mid-gland (arrow). (c) The corresponding axial ADC map demonstrates restricted diffusion (arrow). (d) The corresponding axial DCE image demonstrates hyperenhancement (arrow). The lesion was considered to be PI-RADS score 4. MRI/ultrasound fusion-guided, targeted biopsy revealed Gleason score 4þ3¼7 disease, involving 40% of the specimen. Subsequently in-bore MRI-guided cryoablation via a transperineal approach was performed. (e) Axial and (f) sagittal T2-weighted images demonstrate an area of signal void (arrow), indicative of ice ball, which encompasses the MRI-detected left anterior prostate cancer.

is to assess patients for the presence of distant metastatic disease or local recurrent disease, each requiring different forms of systemic or local therapy. Local recurrence may be amenable to salvage therapy. Systemic recurrence may be an indication for systemic treatment including androgendeprivation therapy or chemotherapy. Transrectal ultrasound (TRUS) has been used for the evaluation of local recurrence with mixed results. The altered anatomy from surgery or radiation, the development of fibrotic tissue, the fact that 30% of recurrent tumours may be isoechoic and that some lesions are distant

from the ultrasound transducer or extend along the bladder wall influence the accuracy of this technique. The use of CT or TRUS biopsy has been questioned in the face of a rising PSA level, as negative results are unreliable and elevated PSA levels usually precede clinical evidence of local recurrence by 1 years. Furthermore, CT imaging is even less sensitive depicting local recurrences of 2 cm3.18 Repeat TRUS with vesico-urethral anastomosis (VUA) needle biopsy may be necessary to document local recurrence in one-third of cases.19 Only approximately 25% of men with post-prostatectomy PSA levels of <1 ng/ml have histological

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confirmation of local recurrence after biopsy of the prostatic fossa.20 In a more contemporary series with biochemical recurrence (BCR) in post-surgical patients, mpMRI can aid in the targeting of TRUS biopsies with 65% of biopsies being positive with a mean PSA of 0.58 ng/ml.21 11 C-choline PET/CT has an advantage to reveal both local recurrent and distant metastatic cancerous lesions. 11Ccholine PET/CT had a sensitivity of 73%, a specificity of 88%, a positive predictive value (PPV) of 92%, a negative predictive value (NPV) of 61%, and an accuracy of 78% for the detection

of clinically suspected recurrent prostate cancer in postsurgical patients13; however, 11C-choline PET/CT is not widely available (Fig 2aed). With the limitations of ultrasound and CT, MRI has been shown to be quite useful in the detection and staging of recurrent prostate tumours.22,23 The use of integrated endorectal and pelvic phased-array coils has led to improved visualisation of the prostatic fossa. The addition of DCE MRI to conventional T2-weighted MRI improves the detection of small local recurrent tumours.

Figure 2 A 60-year-old man with a history of proton beam therapy for prostate cancer presents with BCR of PSA 7.8 ng/ml. His PSA nadir was around 2.5 after radiation. mpMRI at 3 T with an endorectal coil was performed for further evaluation. (a) Axial T2-weighted images demonstrate an area of hypointensity in the left lateral peripheral zone at the apex (arrow). (b) The corresponding DCE image demonstrates hyperenhancement (arrow). (c) The corresponding ADC map demonstrates hypointensity (arrow), indicative of restricted diffusion. (d) The corresponding C-11 choline PET/CT image demonstrates choline avidity (arrow). Findings were consistent with recurrent prostate cancer in the left peripheral apex. Subsequent transperineal needle biopsy revealed adenocarcinoma, Gleason score 4þ3 in the left peripheral zone at the apex, as well as a small focus of Gleason 4 þ 3 just to the right of the patient’s midline. MRI-guided cryoablation via transperineal approach was performed. (e) Axial and (f) sagittal T2-weighted images demonstrate a hockey-stick-shaped area of ice ball (arrow), which encompasses the foci of biopsy-proven prostate cancer. Please cite this article in press as: Woodrum DA, et al., Prostate cancer: state of the art imaging and focal treatment, Clinical Radiology (2017), http://dx.doi.org/10.1016/j.crad.2017.02.010

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Prostate biopsy techniques Ultrasound-guided biopsies The TRUS prostate biopsy has remained the cornerstone of prostate cancer diagnosis dating back to the systematic “sextant” biopsy protocol with three cores per side.24 A meta-analysis of 68 studies led to a recommendation of a more laterally directed schema with 12 cores improving prostate cancer detection rates by a factor of 1.3.25 Using this systematic 12 core TRUS sampling for men undergoing initial biopsy with elevated PSA yields cancer detection rates between 30e55%.26 The false-negative rate for this 12 core schema is of the order of 20e24%27 and repeated 12 core or saturation biopsies show detection rates of 11e47%.28 This is particularly true for men with anteriorly located tumours.29 To improve the accuracy of the sampling, some experts advocate the use of template, transperineal-mapping biopsies to systematically sample all quadrants of the prostate.30 This has been criticised for oversampling of insignificant tumours with risk of additional morbidity and need for general anaesthesia.

MRI-based biopsy techniques In the last decade, increasing evidence supports the use of pre-biopsy mpMRI for significant disease localisation, with intent of addressing the limitations of the systematic biopsy, reducing the detection of low-risk cancers, and improving the detection of clinically significant prostate cancer.30e32 There are three MRI-based biopsy technical approaches.

Cognitive/visual-directed MRI targeted biopsy During TRUS-guided biopsy procedures the operator can estimate the location of MRI suspicious lesions based on prior review of prostate MRI. With appropriate experience, this is straightforward and easy to implement without an upfront equipment investment; however, this cognitive fusion (or visual estimation) based targeted biopsy method is highly operator dependent. This method is prone to error in reliably mapping the MRI suspicious lesion on real-time TRUS and the confirmation of TRUS-guided targeted biopsy needle location over the MRI suspicious lesion is not feasible. In a study of 555 patients by systematic biopsy as well as cognitive fusion-guided targeted biopsy, overall 54% (302/555) of patients were found to have cancer; 82% of them were clinically significant. Systematic biopsy and cognitive fusion-guided targeted biopsy detected 88% and 98% of clinically significant cancers, respectively.33 Cognitive fusion targeted biopsy showed 16% more high-grade cancers and higher mean cancer core lengths than standard systematic biopsy. Cognitive targeted biopsy would only avoid 13% of insignificant tumours. Using a similar visually directed approach for the trans-perineal biopsy, Valerio et al.34 compare this to a software-based targeted biopsy. The software-based, targeted transperineal

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approach found more clinically significant disease than visually directed biopsy, although this was not statistically significant (51.9% versus 44.3%, p¼0.24)34 The current diagnostic ability of visually/cognitively targeted and software-based biopsies seem to be nearly comparable. Ongoing prospective trials hope to confirm these findings, albeit based on those with significant operator experience.

Software-based ultrasound: MRI fusion targeted biopsy Software-based MRI/TRUS fusion-guided biopsy enables the combination of the advantages of real-time TRUS providing better temporal resolution and cost effectiveness, with those of MRI providing better spatial resolution and more accurate cancer detection, and has the potential to improve the detection of clinically significant cancers and for re-biopsy of patients with elevated PSA despite prior benign biopsy results. There are three key tracking methods including (1) image organ-based tracking, (2) electromagnetic sensor-based tracking, and (3) mechanical arm, sensor-based tracking. Image organ (prostate)-based tracking methods fuse prior MRI with real-time ultrasound using a surface-based registration and elastic organ-based deformation algorithm (Urostation, Koelis). MRI suspicious lesions will be brought into the aiming mechanism of the biopsy gun attached to the ultrasound probe. This is relatively inexpensive and allows systemic biopsy; however, confirmation of targeted needle biopsy tracts is retrospective.35 Electromagnetic sensor-based tracking using non-rigid registration algorithm allows real-time spatial tracking of targets and needle location. This system is less operatordependent and allows a free-hand scanning during procedures (UroNav, InVivo; Real-time Virtual Sonography [RVS], Hitachi-Aloka). In a recent prospective study of 1,003 men undergoing a MRI/ultrasound fusion targeted biopsy and concurrent standard biopsy, targeted MRI/ultrasound fusion biopsy was shown to diagnose 30% more high-risk prostate cancer (defined as Gleason score 4 þ 3 or greater) while a combination of standard and targeted biopsies revealed 22% more prostate cancer, mostly (83%) low-risk prostate cancer (defined as Gleason score 3 þ 3 and low volume 3 þ 4).36 A sensor-based tracking system, in which a mechanical tracking arm is attached to a conventional ultrasound probe, allows real-time spatial tracking of targets and needle location (Artemis, Eigen). This system is less operatordependent, but relatively expensive. In a recent retrospective review of 601 men who underwent both MRI/ultrasound fusion targeted biopsy and systematic biopsy, targeted MRI/ultrasound fusion biopsy detected fewer Gleason score 6 prostate cancers (75 versus 121; p<0.001) and more Gleason score 7 prostate cancers (158 versus 117; p<0.001) when compared with systemic biopsy.37 In a review of 105 patients with prior negative biopsies and elevated PSA, MRI/ultrasound fusion targeted biopsy improved detection of clinically significant prostate cancer when compared with systemic biopsy.38 In a recent study of 1,042 men who underwent mpMRI and targeted and systemic biopsies, the addition of systemic

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biopsy to targeted biopsy found 7% (60/825) additional clinically significant cancer.39 These lesions would have been underdiagnosed if mpMRI suspected lesions only were targeted. In a study of 125 consecutive patients who had prebiopsy mpMRI, subsequent MRI/ultrasound fusion biopsy, and subsequently underwent radical prostatectomy, 4% (five of 123) MRI-detected clinically significant prostate cancers were missed at MRI/ultrasound fusion targeted biopsy.40 In a prospective study of 116 MRI-detected lesions in 62 patients who underwent pre-biopsy mpMRI and targeted and systemic biopsies, the highest cancer-detection rates were found for PI-RADS score 5 with a detection rate of 81%.41 In contrast, PI-RADS score 4 had low to moderate cancer-detection rates. Further refinement of PI-RADS scoring criteria may still be necessary to enhance true positives and reduce false positives.

In-bore direct MRI targeted biopsy There are two in-bore direct MRI targeted biopsy approaches including robot assisted, transrectal biopsy (DynaTRIM, InVivo) and transperineal biopsy using a brachytherapy template. The advantage of direct in-bore MRI-guided biopsy is imaging confirmation of targeting of MRI-detected lesions without the need for sophisticated image registration and fusion with live ultrasound images. Transperineal biopsy using a brachytherapy template may reduce the bacterial transmission risk of a transrectal approach for biopsy. In a study of 265 patients with rising PSA despite prior negative TRUS-guided biopsies utilising a robot-assisted transrectal biopsy device (DynaTRIM, InVivo), a detection rate of overall prostate cancer and clinically significant prostate cancer per patient was 41% (108/265) and 87% (94/108), respectively.42 Reporting results from a prospective clinical observational study, Penszkofer et al.101 showed the utility of in-bore prostate biopsies with at least one MRI detected lesion in men with no prior prostate cancer, those undergoing active surveillance monitoring and in men with suspected recurrent cancer following treatment.43 Overall cancer was detected in 56.7% with 48.1% with no prior cancer, 72% of those under active surveillance and 72% of those in whom recurrence was expected. The accuracy of the transperineal in-bore biopsy appears good as demonstrated by analysis of biopsy and post-prostatectomy histopathology.44 MRIdetected targets located in the anterior gland had the highest cancer yield (62.5%). Although these advantages are attractive, this approach is not widely used because it requires upfront investment including MRI compatible equipment, use of scanner time for a longer procedure, higher costs per procedure, and collaboration with the urologist, radiologist, and anaesthesiologist.

Focal thermal ablative therapy options Once prostate cancer is found, localised, and imaged, it is necessary to determine a potential treatment plan.

Standard therapies include radiotherapy, surgery, or androgen deprivation45; however, these therapies have significant risk and morbidity to the patient’s health-related quality of life with potential impact on sexual, urinary, and bowel function.3 Active screening programmes for prostate cancer have enabled earlier identification of low-risk prostate cancer because of related morbidity from standard therapies and are using active surveillance to delay treatment until cancer progression.46 Due to the morbidities of standard therapies, patients and physicians are beginning to examine focal therapies for early treatment. Although focal therapy is still controversial due to the potential multifocality of prostate cancer, limitations of current biopsy strategies, suboptimal staging by accepted imaging modalities, and less than robust prediction models for indolent prostate cancers. In spite of these restrictions focal therapy continues to confront the current paradigm of therapy for low-risk disease.47 Furthermore, prostate cancer recurrence rates after established forms of therapy range from 20e60%.48 In this review, we describe some of the recent advances in focal therapy for native prostate cancer and recurrent prostate cancer where MRI imaging is used to direct focal therapy.

Focal therapy treatments for native prostate cancer Although radical prostatectomy and radiation therapy remain the preferred definitive therapy of choice for men with newly diagnosed prostate cancer and with a life expectancy >10 years,49,50 there is increasing interest in less radical focal methodologies for treatment especially in the watchful waiting population. For this population of lowand intermediate-risk prostate cancer patients, active surveillance may be undesirable from the patient standpoint, yet the complications and co-morbidities associated with standard therapies may seem too great for the patient. This patient-driven interest for a more minimally invasive approach is driving focal therapies for prostate carcinoma in low-risk patients.51 As a result, several minimally invasive thermal ablation methods under direct MRI guidance, most prominently cryotherapy,52 laser ablation,53 and highintensity focused ultrasound (HIFU),54 have been developed and are currently being evaluated.

Selection of patients with native prostate cancer for MRI-guided focal therapy In selecting the appropriate patient for focal therapy of the native prostate gland, it is critical to determine that the patient has localised low-risk disease. With low-risk disease, there is level 1 evidence that implies a lack of benefit from radical therapy.55e57 Patients are targeted for cancer work-up due to rising PSA or nodule on DRE. Patients are further evaluated with a mapping biopsy and/or mpMRI with targeted biopsy. Patients are classified to have low or intermediate prostate cancer with a focal positive lesion on mpMRI, Gleason 4þ3, and PSA <20 ng/ml. To be considered for focal therapy, the target lesion should be confined to one lobe of the prostate.56 Furthermore, the target should

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be visible with the imaging technique that will be used to guide the focal ablation treatment.

MRI-guided cryoablation MRI-guided percutaneous cryoablation combines excellent soft-tissue resolution and ice ball monitoring. Early experience combining cryoablation with MRI has shown a high degree of accuracy in defining normal and frozen tissue on all MRI sequences.58,59 There are few data using MRIguided cryoablation within the native prostate. Two published canine studies demonstrated feasibility and overall safety.60,61 These studies did highlight one limitation of cryoablation, which is that the visualised edge of the ice (0 C) does not represent the ablation margin. The actual ablation margin is best demonstrated with contrast enhancement post-procedure and is actually at the e20 C isotherm, which is just inside the edge of the ice ball. There are two published reports of MRI-guided cryoablation in native prostate glands, each with relatively small numbers (Fig 1).62,63 Gangi et al.63 performed MRI-guided prostate cryoablation in 11 patients using 1.5 T MRI. They had some minor complications of haematuria, dysuria, and urine retention. Additionally, they had one major complication of rectal fistula with spontaneous closure after 3 months. The other study examined 18 patients with two slightly different methodologies.62 The group treated with a more aggressive freezing regimen had better results over time.62 These studies confirm that MRI-guided cryoablation is technically feasible with relative safety; however, more short- and long-term data are needed to assess overall efficacy (Fig 1eef).

MRI thermometry for thermal ablation One of the major advantages associated with MRI guidance of thermal ablations is the MRI thermometry and subsequent dose estimations, which are performed in near real-time and allow for adjustments of treatment parameters and tumour targeting. The thermometry to monitor local temperatures most commonly is accomplished using the known linear dependence of proton resonance frequency (PRF) as a function of temperature. During delivery of ablative energy (generated by ultrasound transducer or laser applicator a series of two-dimensional (2D) phase-sensitive T1-weighted fast spoiled gradient-recalled echo MRI images are acquired.64e66 Based on temperature changes, a thermal dose can be calculated to predict a tissue lethal dose.67

MRI-guided laser ablation Laser-induced interstitial thermal therapy (LITT) uses a locally placed laser fibre to deliver targeted thermal ablation. LITT is inherently MRI compatible making it an obvious choice of ablation technologies to couple with MRI imaging. MRI-based temperature monitoring allows real-time feedback during LITT treatment as both deposition of light energy and MRI signal acquisition can be performed

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simultaneously without degradation in the MRI image.68 Performance of the ablation within the MRI allows the use of post-treatment imaging to verify treatment delivery. Because MRI images clearly depict the prostate anatomy and the surrounding critical structures, MRI is critical for monitoring ablation growth to prevent encroachment onto adjacent critical structures. Two publications also demonstrated feasibility in the canine prostate.69,70 These were beneficial due to showing technical feasibility but also demonstrated correlation of the MRI temperature map with contrast-enhanced T1weighted images. A subsequent study in cadavers demonstrated technical feasibility in the human prostate using 3 T MRI (Fig 3).71 Lee et al.53 published early results on 23 patients treated with focal laser ablation demonstrating promising results. Raz et al.72 described using laser ablation for treatment of two prostate cancer patients at 1.5 T with discharge 3 hours after the procedure.72 These studies demonstrate the potential utility of laser ablation in the prostate; however, more data are needed to determine short- and long-term effects.

Ultrasound- and MRI-guided focused ultrasound ablation Treatment of the prostate with focused ultrasound ablation is not new although the MRI-guided version of the procedure has not, as of yet, been approved by Food and Drug Administration (FDA) in the United States. This treatment modality has been performed with TRUS imaging guidance with success in Europe for many years73,74; however, a major limitation of ultrasound imaging guidance is the difficulty in visualising the focus of cancer, especially if the focus is small. Therefore, the treatment strategy used with ultrasound-guided HIFU is to ablate the entire prostate, or relatively large region where the site of biopsyproven cancer was found using a mapping biopsy and/or mpMRI. This often results in inadequate tumour control or over-ablation of unnecessary normal/neural tissue with potential subsequent morbidity. An early study, using HIFU ablation in prostate by Gelet et al.,75 treated 82 patients who were subsequently followed up for 24-months. These patients also received subsequent radiation treatment. Among these patients, 68% were cancer free at the time of followup. Due to the relatively high complication rates, the treatment device underwent multiple iterations and improvements. A subsequent study, by Gelet et al.,76 demonstrated incontinence and impotency rates around 14% and 61% respectively at 19 months post-treatment. In both studies, major limitations were identified as total procedure time due to a need to cover the entire prostate and inability to monitor temperature elevations or ablation zone expansion. MRI thermal monitoring and localisation of lesions/zones within the prostate should allow optimisation of ablation treatment zone while ablation temperature monitoring should allow improved safety margin in regard to vital adjacent tissues. Currently, there are two MRIintegrated systems using transrectal (Exablate, InSightec,

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Figure 3 Native gland laser ablation performed on a 70-year-old man with rising PSA. (a) mpMRI at 3 T was performed in an indistinct area of mild T2 hypointensity in the right peripheral mid-gland (arrow). (b) In-bore MRI-guided transperineal biopsy of the right peripheral zone with the biopsy needle in place (arrow), which was proven to be positive for Gleason 3þ3 disease. Additional two needles were placed in the left lateral and midline posterior peripheral zones. (c) Temperature mapping phase imaging during the procedure demonstrates appropriate heating. (d) DCE image after laser ablation demonstrates a satisfactory coverage of the ablation zone (arrows) that was positive on biopsy. Two laser applicators are present within the ablation zone.

Haifa, Israel; Fig 4) or transurethral (Profound Medical, Toronto, Canada) transmission routes for treatment of prostate lesions with focused ultrasound technology. The system is fully integrated with the MRI console with temperature feedback control to adjust power, frequency, and rotation rate. Both systems are currently being used in patient trials assessing safety and efficacy for evidence to obtain FDA approval.

Focal therapy treatments for recurrent prostate cancer Recurrences after surgical resection can range from 25e40%, which is usually manifested by rising serum level of PSA.77e79 Approximately 30,000 men will develop BCR with rising PSA after radical prostatectomy each year in the USA.78 A study by Sella et al. utilising MRI performed with an endorectal coil examined the location of recurrences and found 81% occurred as local prostate bed recurrence.80 For those patients who undergo radiotherapy, BCR can range widely between 33 and 63% over 10 years, and contributes another 45,000 men/year with post-radiotherapy recurrent cancer in the USA alone.81,82 Salvage treatments currently available for recurrent prostate cancer include: salvage

radical prostatectomy, salvage radiotherapy, salvage ultrasound-guided HIFU, salvage ultrasound-guided cryoablation, and newly described salvage MRI-guided laser and cryoablation.

Selection of patients with localised recurrent prostate cancer for MRI-guided focal therapy The first issue is to determine whether the rising PSA represents local recurrence, systemic recurrence, or both.79 The second issue in managing patients with BCR of prostate cancer is assessing the risk of cancer treatment versus the risk of further intervention. Overall, rapid PSA rise, shortdisease free interval, and high-grade disease are all poor prognostic indicators with a higher likelihood of systemic recurrence, while slow PSA rise, long disease-free interval, and low-grade disease are better prognostic indicators with a higher likelihood of local recurrence.49,83 Suggested criteria for MRI-guided focal ablative treatment in recurrent prostate cancer are as follows: (1) biopsyproven local recurrent tumour that can be visualised by MRI, (2) absence of distant metastasis confirmed with chest, abdomen, pelvis CT and/or MRI plus bone scintigraphy and/ or 11C-choline PET/CT.50 Although these selection criteria are

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Figure 4 MRI-guided transrectal focused ultrasound ablation of prostate cancer. (a) Axial T2-weighted image demonstrates a small hypointense area in the right peripheral zone consistent with prior biopsy positive Gleason 3þ3 (red arrow). (b) Schematic illustration demonstrates the endorectal treatment transducer (InSightec, Haifa Israel). (c) Software planning map with thermal dose treatment estimation. (d) Post-treatment gadolinium enhanced images demonstrate the ablation zone (Courtesy of www.insightec.com). MRI-guided transrectal focused ultrasound ablation of prostate cancer is currently not approved by FDA.

not perfect, they are helpful in avoiding treatment of what is thought to be a local recurrence, which is really systemic.

Ultrasound-guided cryotherapy for recurrent prostate cancer Ultrasound-guided cryotherapy is currently being used for primary prostate cancer treatment as well as salvage treatment after primary radiotherapy failure. Due to the relative recent development as a treatment modality, there are limited studies on its efficacy. Chin et al.84 reported on 118 patients treated with salvage ultrasound cryotherapy after radiotherapy failure. This study showed a negative biopsy rate of 87% with a median follow-up of 18.6 months. Siddiqui et al.85 presented 15 patients with salvage ultrasound-guided cryotherapy after radical retropubic prostatectomy. Their findings demonstrated a 40% biochemical disease free state (bDFS) at a mean follow-up of 20 months. As cryotherapy devices have evolved with mixed gas technology, smaller cryoprobe size, improved urethral preservation with warmers, better imaging, and increased operator experience, the success rates have improved and complication rates decreased. A recent large study from the COLD cryo on-line data registry reported the 5-year bDFS to be 58.9% by the ASTRO definition of BCR and 54.5% by the

Phoenix definition of BCR.86 For patients treated with salvage ultrasound-guided cryotherapy after primary radiotherapy failure, the most recent reported complication rates are perineal pain (4e14%), mild-moderate incontinence (6e13%), severe incontinence (2e4%), and urethrorectal fistula (1e2%). With the use of urethral warming catheter, the rate of sloughing and urethral stricture has been reduced to near zero. Erectile dysfunction (ED) is still high with rates of 69e86%.87

MRI-guided cryoablation for recurrent prostate cancer MRI-guided cryoablation for recurrent prostate cancer has also been shown feasible and successful in a number of small limited studies. Woodrum et al.62 published a study of 18 patients treated with MRI-guided cryoablation for locally recurrent prostate cancer. The cohort was broken into two groups of nine patients with alteration of the cryoablation technique between the groups.62 The study demonstrated that a tight (5 mm) spacing of cryoneedles, three freezeethaw cycles, and sometimes decreasing the urethral warmer temperature produced better short-term recurrence-free intervals. Additionally, Gangi et al.63 demonstrated successful MRI-guided cryoablation treatment of several patients with recurrent prostate cancer as well. This

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technique offers the advantage that it is not appreciably limited by the prior surgical or radiation treatment to the targeted area.62,63 Using MRI guidance, cryoablation treatment can be tailored to the desired area (Figs 2eef; 5e6).

MRI-guided laser interstitial therapy (LITT) for recurrent prostate cancer Using LITT for recurrent prostate cancer is a relatively recent development. A feasibility study and a case report using 3 T MRI with the Visualase 980 nm diode laser system (Medtronic, Minneapolis, MN, USA) to treat a prostate cancer.88 A small case series was also presented by the same group, which demonstrated the feasibility of treating recurrent prostate cancer with laser ablation (Fig 7).88 One complicating factor with MRI-guided laser ablation in patients with prior surgical resection is the presence of surgical clips, which cause susceptibility artefacts and degrade the MRI-based temperature mapping. Therefore, recurrences within the surgical clips present would be a relative contraindication for this method of treatment.

HIFU for recurrent prostate cancer Salvage HIFU, which targets focused ultrasound energy to a specific area has been used for primary prostate cancer

treatment and for salvage therapy. HIFU achieves cellular death by rising the cellular temperature >60 C causing cellular necrosis. Salvage HIFU is relatively recent treatment modality with limited studies on its efficacy. Three different studies have been published with relatively short follow-up period of 7.4e18.1 months. These studies demonstrated a highly variable bDFS of 25e71%, which was confounded by variable definitions of PSA failure and variable use of hormonal therapy before treatment. The most commonly reported complications are incontinence (10e49.5%), urethral stricture with retention (17e17.6%), erectile dysfunction (66.2e100%), and recto-urethral fistula (3e16%).87,89e91

Follow-up imaging After MRI-guided salvage thermal ablation, the best way to monitor the patient is by measuring serum PSA. PSA levels are expected to be undetectable within several weeks of salvage procedure. Detectable levels of PSA after salvage treatment indicate residual or untreated cancerous lesions. A rise in a previously undetectable or stable postoperative PSA levels during post-treatment follow-up indicate recurrent or possibly metastatic disease. Follow-up imaging is performed at 6 months postprocedure. Laser ablation can leave heat fixation artefacts

Figure 5 MRI-guided cryoablation for recurrent prostate cancer performed on a 69-year-old man with rising PSA after prior brachytherapy treatment 7 years prior. mpMRI at 3 T with an endorectal coil was performed for further evaluation. (a) Axial T2-weighted image demonstrates an indistinct hypointense lesion in the right lateral peripheral zone (arrow). Multiple interstitial brachytherapy seeds are present within the prostate gland bilaterally. (b) The corresponding DCE image demonstrates no abnormal tumour enhancement. Note the patient had been on Lupron for 3 months, which likely decreased the sensitivity. Intraprocedural MRI/ultrasound fusion guided, targeted biopsy from the right peripheral mid-gland was positive for Gleason 4þ4 low volume cancer (see Fig. 1a). (c) Axial and (d) sagittal T2-weighted images demonstrate ice ball coverage of the prostate cancer located in the posterior right prostate (arrow). Please cite this article in press as: Woodrum DA, et al., Prostate cancer: state of the art imaging and focal treatment, Clinical Radiology (2017), http://dx.doi.org/10.1016/j.crad.2017.02.010

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Figure 6 MRI-guided transperineal cryoablation of a recurrent tumour in the seminal vesiculectomy bed in a 67-year-old man with biochemical failure after radical prostatectomy for adenocarcinoma, Gleason 3þ4 14 years ago. PSA increased to 1.5 from 0.88 ng/ml a year ago. mpMRI at 3 T with an endorectal coil demonstrates a nodule in the left seminal vesiculectomy bed (arrows) on (a) axial and (b) sagittal T2-weighted images. (c) The lesion exhibits hyperenhancement (arrow) on the DCE image and (d) restricted diffusion (arrow) on ADC map. TRUS-guided biopsy showed adenocarcinoma, Gleason score 3þ3 from the left seminal vesicle bed. During cryoablation and after saline displacement of the rectum, an ice ball is shown to encompass the recurrent tumour located in the seminal vesiculectomy bed on (e) axial and (f) sagittal T2-weighted images (arrow). Note left ureter with stent in place (arrowhead).

post-ablation, which can make early post-procedural imaging difficult to interpret. Cryoablation has been shown to have some residual ablation zone contrast enhancement when imaging <6 months post-ablation, which resolves at 6 months after imaging.92 Endorectal coil MRI with DCE and DWI is useful for the assessment of prostatic fossa, iliac lymph nodes, and pelvic bones. Mild inflammatory enhancement about the ablation zone without a discrete mass is a common finding after procedure and usually resolves within 3 months after procedure. Persistent or new discrete enhancing nodules on MRI are suspicious for residual or recurrent cancerous lesions. These enhancing

nodules, if still confined in the prostatic bed, may be amenable for repeated MRI-guided salvage ablation.

Challenges Limitations to MRI visualisation of ice ball temperature isotherms A major limitation for MRI-guided cryoablation is that the ice ball isotherms are not readily visualised. The leading edge of the ice ball is well visualised due to very rapid T2

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Figure 7 MRI-guided laser ablation for recurrent prostate cancer in a 65-year-old man with prior radiation therapy. (a) Axial DCE contrastenhanced MRI at 3 T demonstrates abnormal enhancement of the left peripheral mid-gland (arrow). (b) T2-weighted images demonstrates an abnormal contour in the left peripheral zone (arrow). Intraprocedural images of the 15 W laser ablation with double-applicator activation. (c) A magnitude T1-weighted image demonstrates an area of low T1 signal intensity in the area of the ablation (arrow). (d) Corresponding temperature-sensitive phase imaging displaying colour-coded temperature changes (arrow). (e) Based on the temperature-dependent phase image changes, the ablation zone is computed, using the Arrhenius model of thermal tissue damage, and projected back onto the magnitude image as solid orange (arrow).

relaxation of ice protons, but this corresponds to 0 C and may not be lethal. Therefore, it is necessary to carry the edge of the ice beyond the tumour margin by at least 5 mm; however, this approach assumes that ice ball lethal isotherms of e40 C are <5 mm from the leading edge of the ice ball93 and in the presence of complicating factors such as heat transfer from adjacent major vessels or urethral warmers, this assumption may or may not be true.94 Additionally, there are currently no reliable MRIcompatible temperature-monitoring devices to confirm lethal temperatures. MRI performed with ultra-short echo times (UTE) has been demonstrated to be a promising tool in visualising temperature changes within frozen tissues; however, the technique is yet to be applied in clinically.95e97 Confounding the need for good margin coverage is the problem of very restrictive space in and around the prostate bed with close proximity to the rectum, bladder, and external striated urethral sphincter with very little margin for error.

Limitations of MRI thermometry PRF temperature mapping utilises the phenomenon of linear change of resonance frequency of water protons with

temperature. It is a powerful tool in MRI, however, there are certain limitations to the technique due mainly to the fact that these types of thermometry measure phase changes between an initial baseline image and all subsequent images acquired in real time. Ideally, all these images should be in perfect alignment with no motion between them. As a consequence, motion is a large problem where the baseline image alignment is disrupted causing phase registration artefacts. A method that has been proposed to alleviate this is the reference-less temperature mapping.98,99 Another potential issue is the presence of the surgical clips, which can cause metallic artefact resulting in image distortion and signal drop-out, which can severely degrade MRI images. In the native prostate, this is less of an issue, but in the postsurgical prostate bed surgical clip artefact becomes a real problem for phase change-based temperature imaging. The final major limitation with PRF-based temperature mapping is problem with tissue/fat interface. The resonance frequency is only dependent on temperature for water protons. Resonance frequency of protons in fat is unaffected by temperature and therefore the PRF method is much less sensitive to temperature changes in tissues with high fat content, as can be the case with glandular tissue. Some approaches attempt to resolve this issue by the use of the

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so-called Dixon technique to separate MRI signals from fat and water, use of the PRF method on fat-only images and use of phase changes of the fat signal to correct for nontemperature-dependent phase changes.100 This technique, however, has not, as of yet, been applied clinically.

Limitations of MRI availability Access to MRI can be problematic due to the increasing demand of diagnostic imaging; however, as an increasing number of MRI-guided or supported procedures develop, there is a shifting paradigm of thinking that MRI is just used for diagnostic imaging. Within neurosurgery there has been an increasing shift to utilise intraoperative MRI to assist with excision. With the prostate, there has been increasing utilisation of MRI for diagnosis as demonstrated with the publication of PIRADS versions 2 where the importance and nuances of prostate MRI have been laid out.9 From a practical standpoint, this may necessitate working with diagnostic radiology to determine times of decreased demand when MRI-guided procedures can be performed. Initially, it is also important to have a specialised team who are familiar with the MRI environment and the procedure being performed in the MRI until it becomes more routine. All these factors make initiation harder but the imaging guidance and precision that MRI brings to the procedure are significant.

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Conclusions As the most common cancer in men, prostate cancer diagnosis and treatment for new or recurrent disease will demand considerable resources and effort for years to come. MRI plays a seminal role in the management of this disease. MRI and ultrasound fusion for prostate biopsy guidance appears to represent the next step in timely diagnosis and navigation to clinically significant cancers. Although MRI-guided focal ablation of native or recurrent prostate cancer is feasible and rapidly becoming a viable treatment alternative, all focal therapy treatment series suffer from relatively small patient numbers and the need for comparison to established therapies. Additionally, it is critically important that good prospective clinical trials for each be performed to assess the advantage of each treatment modality and to determine the long-term efficacy.

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Please cite this article in press as: Woodrum DA, et al., Prostate cancer: state of the art imaging and focal treatment, Clinical Radiology (2017), http://dx.doi.org/10.1016/j.crad.2017.02.010