- Email: [email protected]
Moving Forward the State of the Art in Prostate Cancer Treatment: Targeted Focal Therapy
urologypracticejournal.com
Moving Forward the State of the Art in Prostate Cancer Treatment: Targeted Focal Therapy E. David Crawford,*,y Kyle O. Rove,z Nelson N. Stone,x M. Scott Lucia,k Al B. Barqawi{ and Francisco G. La Rosa** From the Department of Urology, The Icahn School of Medicine at Mount Sinai, New York, New York (NNS); Department of Pathology (MSL, FGLR), and Division of Urology (KOR, ABB), Section of Urologic Oncology (EDC), University of Colorado, Anschutz Medical Campus, Aurora, Colorado
Abstract
Abbreviations and Acronyms
Introduction: The diagnosis and treatment of prostate cancer have changed dramatically in the prostate specific antigen era. We are now faced with the clinical dilemma of over diagnosis and overtreatment. Targeted focal therapy offers a potential middle ground between the binary choices of active surveillance and the whole gland treatments of radical prostatectomy or radiotherapy. Methods: A PubMedÒ search was performed using the terms “targeted focal therapy,” “focal therapy,” “hemiablation” and “transperineal mapping biopsy” to locate studies and reviews published after 2000 pertaining to targeted focal therapy of the prostate. Key articles were selected and included in this review, which covers the practical aspects of targeted focal therapy for prostate cancer. Results: Three international, multidisciplinary consensus statements were located which provide best practice for patient selection in ongoing and future trials of targeted focal therapy. Other studies located for the review elaborate on the best techniques to properly stage a case of histologically confirmed prostate cancer under consideration for focal therapy and summarize outcomes reported to date in the literature. Conclusions: Phase I and II studies of targeted focal therapy for prostate cancer have demonstrated safety and efficacy. With improved imaging and standardized patient selection criteria, phase III study is under way, perhaps setting the stage for a new era of prostate cancer therapy for many individuals.
3-D = 3-dimensional HIFU = high intensity focused ultrasound MRI = magnetic resonance imaging PSA = prostate specific antigen TRUS = transrectal ultrasound UTI = urinary tract infection
Key Words: prostatic neoplasms; biopsy; ultrasound, high-intensity focused, transrectal; magnetic resonance imaging
Prostate cancer is a disease entity that continues to confound experts and patients because of its long natural history, high prevalence rate, and substantial cause of morbidity and mortality. PSA, heralded as one of the first tumor biomarkers in the 1980s, tripled the detection rate of the disease and identified the majority of locally advanced lesions. Before this point, tumors were large and easily detectable by transrectal ultrasound and
biopsy. Today, through widespread early detection protocols using PSA, many men with apparent indolent disease are being identified (over diagnosed) and subsequently overtreated, and this is estimated to affect between 25% and 85% of men.1 Therefore, the U.S. Preventive Services Task Force recently gave prostate cancer screening with PSA a D rating (discouraging routine use given there is moderate or high certainty that
Submitted for publication April 15, 2014. * Correspondence: Division of Urology, Section of Urologic Oncology, University of Colorado, Anschutz Medical Campus, P.O. Box #6510, Mail Stop #F710, Aurora, Colorado 80045 (e-mail address: [email protected]). y Financial interest and/or other relationship with Genomic Health, Ferring, Janssen and Bayer. z Financial interest and/or other relationship with The Canadian Journal of Urology, UBM Medica and ZS Associates.
x Financial interest and/or other relationship with Janssen Pharmaceuticals, Dendreon, MaxVita LLC, Prologics LLC, Nihon Medi-Physics, Diversified Conference Management, Prostate Conditions Education Council and Bayer. k Financial interest and/or other relationship with 3D Biopsy, LLC. { Financial interest and/or other relationship with Healthtronics Inc. ** No direct or indirect commercial incentive associated with publishing this article.
2352-0779/$36.00 Ó 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION Published by Elsevier
AND
RESEARCH, INC.
http://dx.doi.org/10.1016/j.urpr.2014.05.003 Urology Practice 1 (2014), 156-164
Targeted Focal Therapy for Prostate Cancer
the service has no net benefit or that the harms outweigh the benefits). In addition, the American Urological Association guideline released in 2013 recommends discussing the risks and benefits of screening using shared decision making for men 55 to 69 years old, as well as lengthening the screening interval to every 2 years.2,3 The strategy of active surveillance is used to mitigate overtreatment in men identified as harboring low grade disease. For properly selected men active surveillance is safe, with a low risk of disease progression, and those who opt for later treatment appear to fare just as well as those who receive treatment up front.4,5 The limitations of active surveillance include the need for repeat prostate biopsy, poor performance of PSA kinetics to identify progression, and a paucity of clinical interest in placing patients on active surveillance programs, although improved recognition of overtreatment may be changing this.6 Those not opting for or found inappropriate for active surveillance are offered radical whole gland treatment (radical prostatectomy or radiotherapy), which also concerns patients given the not insignificant rates of urinary, sexual and gastrointestinal side effects that can occur despite advances in technology.7 Furthermore, recent evidence from the PIVOT study suggests that radical prostatectomy for men with PSA less than 10 ng/ml did not prolong survival.8 Targeted focal therapy may offer a middle ground beyond the typical binary approach of all or nothing, serving as a technique that spares the patient full gland therapy but still provides the assurance of lesion eradication.9 This terminology encompasses any ablative treatment approach that leaves some portion of the prostate gland intact. Debate over the merits of focal therapy has persisted since the first reports highlighted its feasibility while preserving urinary and erectile function and suggesting no loss of oncologic control.10,11 With recent improvements in imaging and staging technologies and under the guidance of several consensus panels led by experts in the field, prospectively designed trials with clear patient selection, and well-defined primary outcomes and followup have been published, demonstrating the usefulness and promise of focal therapy for prostate cancer. This review will cover the practical aspects of targeted focal therapy for prostate cancer. We highlight current methods for patient selection, elaborate on the best techniques to properly stage disease in a patient with histologically confirmed prostate cancer considering focal therapy, summarize outcomes reported to date in the literature, and delve into future ongoing studies that are needed. Patient Selection Prostate Specific Antigen The first reports of targeted focal therapy were small and retrospective, and none set limits on preoperative PSA for study inclusion.10,11 Around this time active surveillance protocols were receiving increased recognition, advocating that men meeting D’Amico criteria for low risk disease (PSA less than 10 ng/ml, Gleason score 6 or less, cT2a or less) strongly
157
be considered for active surveillance.4,12 Given the low likelihood of systemic progression in this group, these patients are ideally suited for focal ablation, and the popularity of this idea is borne out in the selection criteria for ongoing studies (table 1). At the University of Colorado focal therapy is limited to patients with a PSA less than 10 ng/ml, Gleason score 3þ4 or less and a percentage of positive cores on transperineal mapping biopsy of less than 20%.13 Some have argued that given the rarity of biochemical failure, metastasis or death in men with low risk prostate cancer, the urological community should investigate whether focal therapy can also be performed in men with intermediate and high risk disease features.9 Notwithstanding the increased interest in focal ablation, there are several limitations to existing technology that make this option less than ideal. Centers that elect to treat just 1 side of the gland, referred to as hemiablation, often rely on PSA or transrectal biopsy results. Several studies have compared preoperative PSA values to radical prostatectomy specimens in an attempt to ascertain whether PSA values might predict multifocality. Djavan et al found that while there were statistically significant differences in PSA density of the transition zone and the ratio of free-to-total PSA, absolute PSA was not a predictor of unifocal vs multifocal disease.14 A retrospective analysis of 525 radical prostatectomy specimens from the ProtecT trial showed that PSA was not significantly different between patients with unifocal (100) vs multifocal (425) disease.15 The authors concluded that the majority of PSA screen detected cancers (with 10 to 12-core transrectal prostate biopsy) are not amenable to focal therapy given the inability to differentiate among patients based on PSA or extended template transrectal biopsy alone. Tumor Focality Prostate cancer is widely considered a multifocal disease, likely secondary to a genetic field effect that affects the glandular epithelium.16 While unifocality was originally considered necessary to offer focal therapy (hence the initial focus on hemiablation), there has been increasing recognition that targeting the so-called index lesion, defined as the largest focus of cancer, may be sufficient to alter the cancer’s course.17 The basis for this argument comes from numerous histopathological studies examining the relationship of index lesion characteristics (size, grade, extent) to oncologic outcomes, showing that the index lesion is the main determinant of prognosis.18 For example, Hall et al found that the index lesion predicted the clinical course despite the presence of secondary foci in 90% of patients.19 These studies also show that the majority (greater than 80%) of secondary foci do not meet criteria for clinical significance (greater than 0.5 cm3).20 As evidenced by the numbers in the ProtecT trials, only a small number of individuals have unifocal (19% to 23%) or unilateral (18% to 23%) disease at prostatectomy.15,21 We also know, for example, that laterality at radical prostatectomy does not appear to influence the risk of biochemical recurrence, suggesting that bilateral disease is not necessarily worse than unilateral disease. Logically one might
158
Targeted Focal Therapy for Prostate Cancer
Table 1. 3 International, multidisciplinary consensus panels on patient selection criteria and outcome definitions23e25
ITF-FLP (2007) Clinical variables: Clinical stage PSA
IWFTI (International Workshop on Focal Therapy and Imaging) e I (2010)
Less than T2a Less than 10 ng/ml; PSA density less than 0.15 ng/ml/ml; PSA vol less than 2 ng/ml/yr Not mentioned Not mentioned
Not mentioned Greater than 10 yrs
12 or More cores
Transperineal mapping (5 mm grid)
Imaging technique
MRI mentioned before þ after treatment
Histopathology
Gleason 3þ3 or less; 20% or less involvement of any core; 7 mm or less involvement of any core; 33% or fewer pos cores Confined to prostate; lesion 12 mm or less in size; lesion 10 mm or less from capsule
Multiparametric MRI experience increasing but still not generally available Gleason 4þ3 or less
Prostate vol Life expectancy Evaluation þ staging: Biopsy technique
Focality
Further study design: Exclusion criteria
Objectives/end points
Treatment failure definitions
Less than T2a Less than 20 ng/ml
IWFTI e II (2013) Less than T2a Less than 15 ng/ml; greater than 15 ng/ml (with caution); PSA density should not be criterion Any, except HIFU (less than 40 ml) Greater than 10 yrs; age should not be criterion Initial systematic TRUS guided biopsy; MRI/TRUS fusion guided targeted biopsies Multiparametric MRI
Gleason 3þ4 or less; % pos cores should be specified; % core involvement should be specified
Unilateral Ca; no apical or anterior lesions
Confined to prostate
Not mentioned
Not mentioned
Posttreatment mapping biopsy; imaging to characterize treatment effects; urinary, bowel þ sexual morbidity rates; rates of biochemical þ clinical progression þ re-treatment; pt reported quality of life measures Not mentioned
Functional outcome (self-reported questionnaires); oncologic outcome (determined by posttreatment biopsy); need for subsequent treatment
Pts with clinically insignificant disease; previous treatment (surgery, radiotherapy, androgen deprivation therapy); extracapsular extension, seminal vesicle invasion, lymph node or bone metastasis; active UTI Focal ablation of clinically significant disease; neg biopsies at 12 mos
Not mentioned
conclude that bilateral disease should not necessarily preclude the possibility of focal therapy. Studies of secondary foci of cancer have shown that its presence does not appear to impact recurrence rates.22 Indeed if the disease process is driven by the single, predominant lesion, then more men may have the option of focal therapy despite the multifocal nature of prostate cancer. However, there are no data available to our knowledge that confirm that treating only the index lesion will result in long-term success. Two phase II trials are under way that will examine outcomes in patients undergoing targeted focal therapy with secondary, untreated foci of cancer (NCT00987675, NCT00877682). A thorough review of these complex issues regarding the definition of and literature involving multifocality has been published by Karavitakis et al.17
Biochemical failure: unable to define; in-field failure: persistent Ca of same/higher grade or need for re-treatment in same area; selection failure: tumor found after focal therapy in area not originally treated
Multifocality is generally the rule in patients with prostate cancer, and better staging of its location, size and extent is key in determining whether individual patients can be safely offered focal treatment. To date, intraprostatic staging before starting treatment has not been possible. Improvements in imaging and better biopsy strategies are critical to further staging before focal therapy. Practical Criteria for Patient Selection There were 3 international multidisciplinary consensus panels that convened in 2007, 2010 and 2013, and each sought to harmonize definitions of focal therapy and patient selection criteria (table 1).23e25 The criteria from the first panel, the ITF-FLP (International Task Force on Prostate Cancer and the
Targeted Focal Therapy for Prostate Cancer
Focal Lesion Paradigm), were fairly conservative, and the authors note that transperineal mapping biopsy may provide greater accuracy. Transperineal mapping biopsy was listed as a requirement for the 2010 panel but again was omitted by the 2013 panel, instead deferring to MRI-TRUS fusion targeted biopsies. This technique is available only at a few centers, and requires specialized, expensive equipment and a radiologist experienced in evaluating multiparametric MRI of the prostate. However, transperineal mapping biopsy should be easily available to all urologists. Staging and Treatment Biopsy Strategies Most patients considering targeted focal therapy will have had a diagnostic 10 to 12-core transrectal ultrasound guided biopsy. While the majority of these will indicate apparent low risk disease, there can be substantial discordance between these diagnostic biopsies and transperineal mapping biopsies or radical prostatectomy specimens, highlighting their inadequacy as intraprostatic staging tools.26 For example, Beauval et al reviewed 10,785 prostatectomy specimens, of which 919 met the criteria for active surveillance on transrectal biopsy.27 Ultimately 34% were upgraded and only 26% had verifiable insignificant disease on radical prostatectomy, implying that 10 to 12-core biopsies may not adequately assess cancer within the gland. There are several extensive and image guided biopsy techniques that may be used to identify patients for focal therapy. No head-to-head trials have suggested that one technique is better than another, and experience and preference will guide the choice of technique to sample/image the prostate. Appropriate biopsy methods should ideally have several characteristics, including the ability to localize cancerous lesions within the gland, to measure extent of cancer and to accurately determine grade. Transrectal saturation biopsy techniques suffer from a lack of uniform gland coverage, and while there is increased sampling density, repeatable localization is difficult without a template.28 Han et al examined the repeatability and glandular coverage of urologists performing freehand transrectal prostate biopsies on a male pelvic simulation model
159
compared to a robotic arm.29 Urologists tended to under sample a significant portion of the prostate compared to the robot arm. Targeting specific regions varied by 9 mm for humans vs only 1 mm for the robot. Similarly, transperineal biopsy without the use of a localization grid (ie freehand) may improve anterior lesion detection but is likely affected by the same lack of accurate localization and repeatability.30 Transperineal mapping biopsies with a 5 mm grid offer an excellent biopsy based method of staging.31,32 Table 2 shows the results of transperineal mapping biopsy studies to date. Hossack et al performed 414 transperineal or 718 transrectal biopsies before prostatectomy and found the transperineal biopsy detected proportionally more anterior tumors (16.2% vs 12%), identifying them at a smaller size (1.4 vs 2.1 cm3) and stage.33 Our group reported that 180 men with apparent low stage prostate cancer on transrectal biopsy had a substantial rate of upgrading (increase in Gleason score in 27%) and up staging (increase in laterality in 46%) at the transperineal mapping biopsy.34 This further demonstrates the inability of extended template transrectal biopsies to provide adequate data to proceed to focal therapy. In another study the correlation of transperineal mapping in 25 patients to whole mounted radical prostatectomy specimens revealed 64 separate lesions, 25 with clinically significant volumes (mean 1.13 cm3) and 39 with insignificant volumes (mean 0.09 cm3).35 Of the 64 lesions 18 were missed by transperineal mapping biopsy but only 1 was considered significant (Gleason score 8, volume 0.02 cm3). This missed lesion was identified in a patient with another clinically significant lesion that was detected at transperineal mapping biopsy. Transperineal mapping biopsy is performed as a day surgery procedure with the patient under conscious sedation or general anesthesia in the operative suite. Patients receive a dose of prophylactic antibiotics before the procedure. They are placed in the dorsal lithotomy position and local anesthetic is injected into the perineum. A Foley catheter is placed for the duration of the procedure and removed at the end. An ultrasound transducer is placed in the rectum, mounted to accessory equipment for probe stabilization, stepwise linear movement and 3-D image acquisition (BK Medical Flex Focus, Herlev, Denmark). A brachytherapy grid with 5 mm spacing is used as a template. Fiduciary golden markers are placed midway between the apex
Table 2. Results of transperineal mapping biopsy for transrectal biopsy detected unilateral disease or prior negative biopsy for selected studies References
No.
Indication
Median Biopsy Core Count
Bilat Disease/Ca Rate (%)*
Gleason Upgrade 7 or Greater (%)
Active Surveillance Exclusion (%)
Retention Rate (%)y
Onik G: J Clin Oncol 2009; 27: 4321 Barzell WE: J Urol 2012; 188: 762 Taira AV: Prostate Cancer Prostatic Dis 2010; 13: 71 Pal RP: BJU Int 2012; 109: 367 Nafie S: World J Urol 2013; Epub ahead of print Bittner N: J Urol 2013; 190: 509
180 124 373
Unilat disease Unilat disease Prior neg biopsy
50 89.7 55e58
61.1 85 75.9
22.7 Not reported 55.3
69.4 41e80 86.4e91.4
7.7 3 29
40 122
Prior neg biopsy Prior neg biopsy
36 36
41.7 58
41.7 61
71.4 79
485
Prior neg biopsy
59
46.6
57.1
86.7
2.5 5 27
*Bilateral disease applies to studies with an indication of unilateral disease and cancer rate applies to those studying mapping biopsy in setting of prior negative biopsies. y Refers to those patients who required catheter drainage for 24 hours or more.
160
Targeted Focal Therapy for Prostate Cancer
and base on either side of the urethra. These markers allow precision targeting and alignment of specific areas of the prostate during future focal therapy. Transperineal biopsies are obtained at 5 mm intervals using a standard 18-gauge biopsy gun. Deeper (base) vs shallow (apex) passes at the same grid position are performed to ensure complete base to apex gland coverage, and each biopsy is labeled with corresponding xeyez coordinates. Transperineal mapping biopsy as a staging procedure is safe, with multiple studies demonstrating no UTIs, low rates of self-limited hematuria, occasional acute urinary retention requiring temporary urethral catheter (3.7% in one series, 3.2% in our series) and no decrease in quality of life measures.34,36 However, transperineal biopsies are not commonly performed in the United States. They take considerably longer to perform than a transrectal ultrasound guided biopsy, they typically require a general or intravenous anesthetic (although some have successfully adapted the procedure to an office setting), and they are expensive due to operating room and pathology processing costs. Instrumentation for transrectal biopsy was developed more than 25 years ago, while the technology used for transperineal mapping biopsy has been adapted from brachytherapy and cryoablation platforms, making the procedure cumbersome to perform. Imaging Techniques Most centers investigating focal therapy now include 3T multiparametric MRI protocols (including diffusion weighted imaging, dynamic contrast enhancement and spectroscopy to improve on T2 images alone) as part of study parameters before and after focal therapy. The reported sensitivity and specificity vary, but most recent series put both at greater than 85% to 90% with negative regions having a 95% probability of being free of clinically significant cancer.37 Multiparametric MRI has good sensitivity to detect larger high grade lesions, but is more limited for smaller tumors and low grade cancers. Prostate MRI should not be obtained until 6 to 8 weeks after biopsy or treatment given the possibility of bleeding artifact. MRI-TRUS fusion targeted biopsies have recently become possible with groups demonstrating improved sampling of suspicious lesions while perhaps minimizing the overall number of biopsies required to characterize a lesion.38e41 Urologists and interventional radiologists have used the images with the lesions demarcated to perform cognitive registration. Several manufacturers now market a package system in which a localization process (for example, electromagnetic) tracks the position of the probe within the rectum while simultaneously overlaying the MRI and ultrasound images. A biopsy guide allows the operator to target the lesion using a transrectal or transperineal approach. Vourganti et al studied 195 men with negative TRUS biopsy who had 3T endorectal coil MRI.42 Lesions were targeted with MRI-TRUS fusion biopsy. In addition, all patients underwent repeat standard 12-core transrectal ultrasound biopsy. Of the previous negative biopsies 73 (37%) were found to have cancer using the MRI-TRUS fusion biopsy combined with 12-core
transrectal ultrasound biopsy. High grade cancer (Gleason score 8þ) was discovered in 21 men (11%), all of whom had disease detected with MRI-TRUS fusion biopsy. Standard transrectal ultrasound biopsy missed 12 of these high grade cancers (55%). On multivariate analysis only PSA density and MRI suspicion level remained significant predictors of cancer. Availability of all the necessary technology and expertise at various centers of excellence is still fairly limited but is expanding as interest grows. Treatment Modalities To date, most focal therapy trials have focused on cryoablation or HIFU (currently approved for use in Europe but for investigational use only in the United States). Preliminary reports on focal radiotherapy (external beam or brachytherapy) have been published as well.43 Note that patient selection for focal radiotherapy trials is believed to be slightly different than for HIFU or cryotherapy (emphasis on unilateral disease, prostate size less than 60 cm3).44 The American Urological Association recognized cryotherapy for localized prostate cancer as a standard treatment option in 1996. Current devices are labeled third generation, and use urethral warmers, a combination of argon (cooling) and helium (warming) gases, taking advantage of the Joule-Thomson effect, and transrectal ultrasound guidance. At our center we use cryotherapy in patients undergoing targeted focal therapy for prostate cancer. We typically target the index lesion as opposed to hemiablation or hockey stick ablation patterns. With the patient in an exaggerated lithotomy position, the same 5 mm template guide used to perform transperineal mapping biopsies is placed on the perineum. We use the results from transperineal mapping biopsy to plan the areas of the prostate to treat focally (fig. 1). A multifrequency biplanar transrectal ultrasound probe on a stepper is used for visualization of the prostate and surrounding structures. Local anesthesia is administered to the perineum. Temperature monitors are placed near Denonvilliers fascia, the external urinary sphincter or neurovascular bundles to monitor for the
Figure 1. Demonstration of transperineal mapping biopsy results plotted into 3-D planning software used before targeted focal therapy.
Targeted Focal Therapy for Prostate Cancer
161
depicts a cross section of the actual kill zone (corresponding to the target temperature of 40C) and the visible affected zone on ultrasound for modern (1.47 mm, 17 gauge) probes in a 1-probe and 3-probe setup. Targeted focal interstitial laser ablation guided by MRI thermal imaging has been reported and we are in the process of publishing our experience with 9 patients.45 The target coordinates are ablated and monitored using fusion of real-time MRI and ultrasound imaging. This is done as a day surgery procedure and allows for precise ablation of the cancer foci. Thus, this technique has even less potential for collateral damage than cryotherapy.
Focal Therapy Outcomes The 2 original focal therapy series by Onik46 and Bahn47 et al have since reported longer followup but these studies suffer from a lack of standardized or comprehensive patient selection criteria and a retrospective nature. Phase I and II studies have been reported demonstrating safety and adequate efficacy (table 3). Ahmed et al reported on 42 men, age 45 to 80 years, who underwent HIFU for unifocal and multifocal prostate cancer identified on transperineal mapping biopsy and/or multiparametric MRI, with the primary end points of adverse events, urinary symptoms and erectile function.48 One man was admitted to the hospital with acute urinary retention, another had urethral stricture, 9 (22%) had self-limited dysuria, 14 (34%) had debris in the urine and 7 (17%) had UTI. Of 35 men with adequate baseline erectile function (89%, 95% CI 73e97) 31 had erections sufficient for penetration 12 months after targeted focal therapy. Overall 40 patients were pad-free at baseline and were able to return to a pad-free state by 3 months. No evidence of disease was found in 39 of 41 patients on MRI at 12 months, with 4 having undergone a repeat focal therapy session. One man died of pneumonia (3 months after treatment, considered unrelated) and was excluded from the analysis.
Figure 2. Single probe setup (A) and 3-probe setup (B). Note that zone that reaches kill temperature is about 4 mm smaller on each side than visibly affected area. Illustration by Kyle Rove, adapted from data by Oncura, Inc.
appropriate level of freezing and to avoid thermal damage to these sensitive structures (the temperature should remain greater than 15C), even if our intended target is not adjacent to these structures. Cryoneedles are inserted under ultrasound visualization in the area of concern as highlighted by focal planning software that coordinates positive mapping biopsy location, grade and size with the previously registered ultrasound images. Appropriate registration (alignment) is performed using the previously placed fiducial markers. Flexible cystoscopy is performed to visualize the urethra and bladder for needles or thermocouples so that they can be moved before starting the freezing cycles. Lastly, a urethral warmer is placed under cystoscopic guidance. Freezing is performed in an anterior-toposterior direction (if more than 1 probe is used, to maintain visibility) down to 40C for 2 freeze-thaw cycles. Figure 2 Table 3. Results of select focal therapy trials
References
No. Treatment
Nguyen PL: J Urol 318 MRI brachytherapy 2012; 188: 1151 Eisenberg ML: Urology 19 Cryoablation 2008; 72: 1315 Truesdale MD: Cancer J 77 Cryoablation 2010; 16: 544 de Castro Abreu AL: J 25 Salvage cryoablation Endourol 2011; 26: A208 Bahn et al47 25 Cryoablation Ellis DS: Urology 2007; 70: 9 60 Cryoablation Onik G: Urology 2007; 70: 16 55 Cryoablation Ahmed HU: Cancer 39 HIFU 2012; 118: 4148 El Fegoun AB: Int Braz 100 HIFU J Urol 2011; 37: 213
Focal Zone
Biochemical Mos Disease-Free Residual Followup Survival (%) Disease (%)
Urinary Incontinence Erectile (%) Function (%) Fistula (%)
Periphery
62
78
Not reported Not reported Not reported
Not reported
Hemiablation
18
79
10
5.2
Not reported
0
Hemiablation
24
80
40
0
Not reported
Not reported
Hemiablation
31
54
8
5
95
0
Hemiablation Hockey stick Focal Hemiablation
70 12 42 17
92.9 80 95 49
4 40 13 44
0 0 4 5
88.8 70.6 85 95
0 0 Not reported 0
8
0
Not reported
Not reported
Hemiablation 126
38
162
Targeted Focal Therapy for Prostate Cancer
One of the more stringent studies currently under way aims to enroll 140 men with transperineal mapping biopsies before and after focal therapy with HIFU combined with quality of life measures.49 The primary outcome in this study is the absence of clinically significant disease on repeat mapping biopsy. Most studies use 10 to 12-core transrectal biopsies or multiparametric MRI at 1 year to monitor disease status. While PSA is closely followed in studies, there are no agreed-upon definitions of biochemical failure given that viable prostate tissue remains after focal therapy. With regard to following PSA after targeted focal therapy, the magnitude of decrease in PSA after focal ablation will depend on the amount of tissue ablated relative to the remaining prostate. Ideally a stable nadir will be achieved. Figure 3 depicts a flow chart of how to select appropriate candidates for focal therapy, and suggests subsequent followup and disease monitoring. Ongoing trials have begun to differentiate among in-field failures (at site of treatment), patient selection failures (clinically significant cancer found outside the treatment area that was previously missed) and the need for repeat treatment. Particular emphasis is also placed on quality of life measures
(urinary, erectile function, anxiety). As shown in the systematic review by Valerio et al,50 we are on the cusp of multiple, prospectively designed trials that are now coming to fruition. New Directions While the current instrumentation for transperineal mapping biopsy yields superior results compared to transrectal biopsy, it is by no means as accurate as it could be. The biopsy needle used was developed more than 30 years ago for transrectal application. A needle designed to take 1 core from apex to base is needed to fully take advantage of the accurate localization potential of the transperineal biopsy approach. Updated 3-D software is required to record the exact position of each biopsy site so the clinician will have an accurate location of the positive sites when applying focal ablation. Lastly, it will no longer be adequate to put a longer specimen on a piece of TelfaÒ and place it in formalin. A pathology receptacle device is required that maintains the integrity of the core so pathology reporting is also accurate.
Figure 3. Clinical pathway for selecting, treating and following appropriate patients with prostate cancer for targeted focal therapy
Targeted Focal Therapy for Prostate Cancer
Conclusions Phase I and II studies of targeted focal therapy for prostate cancer have demonstrated safety and efficacy. With improved imaging, new MRI-TRUS fusion targeted biopsies and standardized patient selection criteria, phase III study is under way, perhaps setting the stage for a new era of prostate cancer therapy for many individuals. References 1. Bangma CH, Roemeling S and Schröder FH: Overdiagnosis and overtreatment of early detected prostate cancer. World J Urol 2007; 25: 3. 2. Moyer VA: Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012; 157: 120. 3. Carter HB, Albertsen PC, Barry MJ et al: Early Detection of Prostate Cancer: AUA Guideline. Available at www.auanet.org/common/pdf/education/ clinical-guidance/Prostate-Cancer-Detection.pdf. Accessed April 2, 2014. 4. Dall’Era MA, Albertsen PC, Bangma C et al: Active surveillance for prostate cancer: a systematic review of the literature. Eur Urol 2012; 62: 976. 5. Klotz L: Active surveillance, quality of life, and cancer-related anxiety. Eur Urol 2013; 64: 37. 6. Cooperberg M, Broering J and Carroll PR: Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol 2010; 28: 1117. 7. Nam RK, Cheung P, Herschorn S et al: Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer: a population-based cohort study. Lancet Oncol 2014; 15: 223. 8. Wilt TJ, Brawer MK, Jones KM et al: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012; 367: 203. 9. Ward JF, Rewcastle JC, Ukimura O et al: Focal therapy for the treatment of localized prostate cancer: a potential therapeutic paradigm shift awaiting better imaging. Curr Opin Urol 2012; 22: 104. 10. Onik G, Narayan P, Vaughan D et al: Focal “nerve-sparing” cryosurgery for treatment of primary prostate cancer: a new approach to preserving potency. Urology 2002; 60: 109. 11. Bahn DK, Silverman P, Lee F et al: Focal prostate cryoablation: initial results show cancer control and potency preservation. J Endourol 2006; 20: 688. 12. Klotz L: Active surveillance with selective delayed intervention: using natural history to guide treatment in good risk prostate cancer. J Urol, suppl., 2004; 172: S48. 13. Barqawi AB, Stoimenova D, Krughoff K et al: Targeted focal therapy in the management of organ confined prostate cancer. J Urol 2014; Epub ahead of print. 14. Djavan B, Susani M, Bursa B et al: Predictability and significance of multifocal prostate cancer in the radical prostatectomy specimen. Tech Urol 1999; 5: 139. 15. Catto JW, Robinson MC, Albertsen PC et al: Suitability of PSA-detected localised prostate cancers for focal therapy: experience from the ProtecT study. Br J Cancer 2011; 105: 931. 16. Jones TD, Wang M, Eble JN et al: Molecular evidence supporting field effect in urothelial carcinogenesis. Clin Cancer Res 2005; 11: 6512. 17. Karavitakis M, Ahmed HU, Abel PD et al: Tumor focality in prostate cancer: implications for focal therapy. Nat Rev Clin Oncol 2010; 8: 48. 18. Wise AM, Stamey TA, McNeal JE et al: Morphologic and clinical significance of multifocal prostate cancers in radical prostatectomy specimens. Urology 2002; 60: 264. 19. Hall GS, Kramer CE and Epstein JI: Evaluation of radical prostatectomy specimens: a comparative analysis of sampling methods. Am J Surg Pathol 1992; 16: 315. 20. Villers A, McNeal JE, Freiha FS et al: Multiple cancers in the prostate. Morphologic features of clinically recognized versus incidental tumors. Cancer 1992; 70: 2313.
163
21. Iczkowski KA, Hossain D, Torkko KC et al: Preoperative prediction of unifocal, unilateral, margin-negative, and small volume prostate cancer. Urology 2008; 71: 1166. 22. Noguchi M, Stamey TA, McNeal JE et al: Prognostic factors for multifocal prostate cancer in radical prostatectomy specimens: lack of significance of secondary cancers. J Urol 2003; 170: 459. 23. Eggener SE, Scardino PT, Carroll PR et al: Focal therapy for localized prostate cancer: a critical appraisal of rationale and modalities. J Urol 2007; 178: 2260. 24. de la Rosette J, Ahmed H, Barentsz J et al: Focal therapy in prostate cancerereport from a consensus panel. J Endourol 2010; 24: 775. 25. van den Bos W, Muller BG, Ahmed H et al: Focal therapy in prostate cancer: international multidisciplinary consensus on trial design. Eur Urol 2014; 65: 1078. 26. Sinnott M, Falzarano SM, Hernandez AV et al: Discrepancy in prostate cancer localization between biopsy and prostatectomy specimens in patients with unilateral positive biopsy: implications for focal therapy. Prostate 2011; 72: 1179. 27. Beauval JB, Ploussard G, Soulié M et al: Pathologic findings in radical prostatectomy specimens from patients eligible for active surveillance with highly selective criteria: a multicenter study. Urology 2012; 80: 656. 28. Falzarano SM, Zhou M, Hernandez AV et al: Can saturation biopsy predict prostate cancer localization in radical prostatectomy specimens: a correlative study and implications for focal therapy. Urology 2010; 76: 682. 29. Han M, Chang D, Kim C et al: Geometric evaluation of systematic transrectal ultrasound guided prostate biopsy. J Urol 2012; 188: 2404. 30. Novara G, Boscolo Berto R, Lamon C et al: Detection rate and factors predictive the presence of prostate cancer in patients undergoing ultrasonography-guided transperineal saturation biopsies of the prostate. BJU Int 2010; 105: 1242. 31. Barzell WE, Whitmore WF III and Andriole G: Transperineal template guided saturation biopsy of the prostate: rationale, indications and technique. Urol Times 2003; 32: 41. 32. Barzell W and Melamed M: Appropriate patient selection in the focal treatment of prostate cancer: the role of transperineal 3-dimensional pathologic mapping of the prostateda 4-year experience. Urology, suppl., 2007; 70: S27. 33. Hossack T, Patel MI, Huo A et al: Location and pathological characteristics of cancers in radical prostatectomy specimens identified by transperineal biopsy compared to transrectal biopsy. J Urol 2012; 188: 781. 34. Barqawi AB, Rove KO, Gholizadeh S et al: The role of 3-dimensional mapping biopsy in decision making for treatment of apparent early stage prostate cancer. J Urol 2011; 186: 80. 35. Crawford ED, Rove KO, Barqawi AB et al: Clinical-pathologic correlation between transperineal mapping biopsies of the prostate and threedimensional reconstruction of prostatectomy specimens. Prostate 2013; 73: 778. 36. Losa A, Gadda GM, Lazzeri M et al: Complications and quality of life after template-assisted transperineal prostate biopsy in patients eligible for focal therapy. Urology 2013; 81: 1291. 37. Villers A, Lemaitre L, Haffner J et al: Current status of MRI for the diagnosis, staging and prognosis of prostate cancer: implications for focal therapy and active surveillance. Curr Opin Urol 2009; 19: 274. 38. Ouzzane A, Puech P, Lemaitre L et al: Combined multiparametric MRI and targeted biopsies improve anterior prostate cancer detection, staging, and grading. Urology 2011; 78: 1356. 39. Pinto PA, Chung PH, Rastinehad AR et al: Magnetic resonance imaging/ ultrasound fusion guided prostate biopsy improves cancer detection following transrectal ultrasound biopsy and correlates with multiparametric magnetic resonance imaging. J Urol 2011; 186: 1281. 40. Kuru TH, Roethke MC, Seidenader J et al: Critical evaluation of magnetic resonance imaging targeted, transrectal ultrasound guided transperineal fusion biopsy for detection of prostate cancer. J Urol 2013; 190: 1380. 41. Walton Diaz A, Hoang AN, Turkbey B et al: Can magnetic resonanceultrasound fusion biopsy improve cancer detection in enlarged prostates? J Urol 2013; 190: 2020. 42. Vourganti S, Rastinehad A, Yerram NK et al: Multiparametric magnetic resonance imaging and ultrasound fusion biopsy detect prostate cancer in
164
43. 44.
45.
46.
Targeted Focal Therapy for Prostate Cancer
patients with prior negative transrectal ultrasound biopsies. J Urol 2012; 188: 2152. Cosset JM, Cathelineau X, Wakil G et al: Focal brachytherapy for selected low-risk prostate cancers: a pilot study. Brachytherapy 2013; 12: 331. Langley S, Ahmed HU, Qaisieh Al B et al: Report of a consensus meeting on focal low dose rate brachytherapy for prostate cancer. BJU Int 2012; 109: 7. Raz O, Haider MA, Davidson SR et al: Real-time magnetic resonance imaging-guided focal laser therapy in patients with low-risk prostate cancer. Eur Urol 2010; 58: 173. Onik GM, Vaughan D, Lotenfoe R et al: The “male lumpectomy”: focal therapy for prostate cancer using cryoablation results in 48 patients with at least 2-year follow-up. Urol Oncol 2008; 26: 500.
47. Bahn D, de Castro Abreu AL, Gill IS et al: Focal cryotherapy for clinically unilateral, low-intermediate risk prostate cancer in 73 men with a median follow-up of 3.7 years. Eur Urol 2012; 62: 55. 48. Ahmed HU, Hindley RG, Dickinson L et al: Focal therapy for localised unifocal and multifocal prostate cancer: a prospective development study. Lancet Oncol 2012; 13: 622. 49. Dickinson L, Ahmed HU, Kirkham AP et al: A multi-centre prospective development study evaluating focal therapy using high intensity focused ultrasound for localised prostate cancer: the INDEX study. Contemp Clin Trials 2013; 36: 68. 50. Valerio M, Ahmed HU, Emberton M et al: The role of focal therapy in the management of localised prostate cancer: a systematic review. Eur Urol 2013; Epub ahead of print.
Editorial Commentary Remember when we used to argue about whether radical surgery was better than external beam radiation for prostate cancer? The consensus back then was that regardless of your bias, whole gland treatment was still needed. This article by Crawford et al is one of many that I am sure will sprout up in the next few years presenting data that focal therapy of the prostate is a reasonable option for many men with early stage disease. As others have shown, low risk prostate cancer is diagnosed in about half of the men undergoing screening.1 The concern with focal therapy, as indicated in this article, is that nearly 30% of men with presumed low risk disease harbor high grade cancer that is unrepresented on the biopsy. With the ability of genomics2 and new age multiparametric MRI scanning,3 clinicians may be able to be more precise about patient selection and evaluation for focal therapy strategies. However, there will still be a subset of men who will be under treated and at risk for relapse. What is not currently known is the salvage rate in these men, and if we are burning any bridges (or freezing any tunnels) by using focal therapy as an initial approach. Having performed many focal cryoablations during the last decade, it is clear to me that this therapy has a definite role in eradicating cancer and preserving function. I continue
to see these men many years after therapy without the need for traditional surgery or radiation. Crawford et al have provided a valuable review of the data in phase I and II studies and of the consensus statements. The optimal therapy for these patients is still unknown and debate will continue as to which approach is best or if any treatment is needed at all. Aaron E. Katz Department of Urology Winthrop University Hospital and Stony Brook School of Medicine Garden City, New York References 1. Klotz L and Emberton M: Management of low risk prostate cancer-active surveillance and focal therapy. Nat Rev Clin Oncol 2014; 11: 324. 2. Fraser M, Berlin A, Bristow RG et al: Genomic, pathological, and clinical heterogeneity as drivers of personalized medicine in prostate cancer. Urol Oncol 2014; Epub ahead of print. 3. Anderson ES, Margolis DJ, Mesko S et al: Multiparametric MRI identifies and stratifies prostate cancer lesions: implications for targeting intraprostatic targets. Brachytherapy 2014; 13: 292.
Reply by Authors In addition to genomics and multiparametric MRI, we also believe precise prostate mapping by biopsy will greatly improve identification and targeting of small regions within
the prostate. Individually or in combination, these new modalities will alter the surveillance and treatment landscape.
Moving Forward the State of the Art in Prostate Cancer Treatment: Targeted Focal Therapy E. David Crawford,*,y Kyle O. Rove,z Nelson N. Stone,x M. Scott Lucia,k Al B. Barqawi{ and Francisco G. La Rosa** From the Department of Urology, The Icahn School of Medicine at Mount Sinai, New York, New York (NNS); Department of Pathology (MSL, FGLR), and Division of Urology (KOR, ABB), Section of Urologic Oncology (EDC), University of Colorado, Anschutz Medical Campus, Aurora, Colorado
Abstract
Abbreviations and Acronyms
Introduction: The diagnosis and treatment of prostate cancer have changed dramatically in the prostate specific antigen era. We are now faced with the clinical dilemma of over diagnosis and overtreatment. Targeted focal therapy offers a potential middle ground between the binary choices of active surveillance and the whole gland treatments of radical prostatectomy or radiotherapy. Methods: A PubMedÒ search was performed using the terms “targeted focal therapy,” “focal therapy,” “hemiablation” and “transperineal mapping biopsy” to locate studies and reviews published after 2000 pertaining to targeted focal therapy of the prostate. Key articles were selected and included in this review, which covers the practical aspects of targeted focal therapy for prostate cancer. Results: Three international, multidisciplinary consensus statements were located which provide best practice for patient selection in ongoing and future trials of targeted focal therapy. Other studies located for the review elaborate on the best techniques to properly stage a case of histologically confirmed prostate cancer under consideration for focal therapy and summarize outcomes reported to date in the literature. Conclusions: Phase I and II studies of targeted focal therapy for prostate cancer have demonstrated safety and efficacy. With improved imaging and standardized patient selection criteria, phase III study is under way, perhaps setting the stage for a new era of prostate cancer therapy for many individuals.
3-D = 3-dimensional HIFU = high intensity focused ultrasound MRI = magnetic resonance imaging PSA = prostate specific antigen TRUS = transrectal ultrasound UTI = urinary tract infection
Key Words: prostatic neoplasms; biopsy; ultrasound, high-intensity focused, transrectal; magnetic resonance imaging
Prostate cancer is a disease entity that continues to confound experts and patients because of its long natural history, high prevalence rate, and substantial cause of morbidity and mortality. PSA, heralded as one of the first tumor biomarkers in the 1980s, tripled the detection rate of the disease and identified the majority of locally advanced lesions. Before this point, tumors were large and easily detectable by transrectal ultrasound and
biopsy. Today, through widespread early detection protocols using PSA, many men with apparent indolent disease are being identified (over diagnosed) and subsequently overtreated, and this is estimated to affect between 25% and 85% of men.1 Therefore, the U.S. Preventive Services Task Force recently gave prostate cancer screening with PSA a D rating (discouraging routine use given there is moderate or high certainty that
Submitted for publication April 15, 2014. * Correspondence: Division of Urology, Section of Urologic Oncology, University of Colorado, Anschutz Medical Campus, P.O. Box #6510, Mail Stop #F710, Aurora, Colorado 80045 (e-mail address: [email protected]). y Financial interest and/or other relationship with Genomic Health, Ferring, Janssen and Bayer. z Financial interest and/or other relationship with The Canadian Journal of Urology, UBM Medica and ZS Associates.
x Financial interest and/or other relationship with Janssen Pharmaceuticals, Dendreon, MaxVita LLC, Prologics LLC, Nihon Medi-Physics, Diversified Conference Management, Prostate Conditions Education Council and Bayer. k Financial interest and/or other relationship with 3D Biopsy, LLC. { Financial interest and/or other relationship with Healthtronics Inc. ** No direct or indirect commercial incentive associated with publishing this article.
2352-0779/$36.00 Ó 2014 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION Published by Elsevier
AND
RESEARCH, INC.
http://dx.doi.org/10.1016/j.urpr.2014.05.003 Urology Practice 1 (2014), 156-164
Targeted Focal Therapy for Prostate Cancer
the service has no net benefit or that the harms outweigh the benefits). In addition, the American Urological Association guideline released in 2013 recommends discussing the risks and benefits of screening using shared decision making for men 55 to 69 years old, as well as lengthening the screening interval to every 2 years.2,3 The strategy of active surveillance is used to mitigate overtreatment in men identified as harboring low grade disease. For properly selected men active surveillance is safe, with a low risk of disease progression, and those who opt for later treatment appear to fare just as well as those who receive treatment up front.4,5 The limitations of active surveillance include the need for repeat prostate biopsy, poor performance of PSA kinetics to identify progression, and a paucity of clinical interest in placing patients on active surveillance programs, although improved recognition of overtreatment may be changing this.6 Those not opting for or found inappropriate for active surveillance are offered radical whole gland treatment (radical prostatectomy or radiotherapy), which also concerns patients given the not insignificant rates of urinary, sexual and gastrointestinal side effects that can occur despite advances in technology.7 Furthermore, recent evidence from the PIVOT study suggests that radical prostatectomy for men with PSA less than 10 ng/ml did not prolong survival.8 Targeted focal therapy may offer a middle ground beyond the typical binary approach of all or nothing, serving as a technique that spares the patient full gland therapy but still provides the assurance of lesion eradication.9 This terminology encompasses any ablative treatment approach that leaves some portion of the prostate gland intact. Debate over the merits of focal therapy has persisted since the first reports highlighted its feasibility while preserving urinary and erectile function and suggesting no loss of oncologic control.10,11 With recent improvements in imaging and staging technologies and under the guidance of several consensus panels led by experts in the field, prospectively designed trials with clear patient selection, and well-defined primary outcomes and followup have been published, demonstrating the usefulness and promise of focal therapy for prostate cancer. This review will cover the practical aspects of targeted focal therapy for prostate cancer. We highlight current methods for patient selection, elaborate on the best techniques to properly stage disease in a patient with histologically confirmed prostate cancer considering focal therapy, summarize outcomes reported to date in the literature, and delve into future ongoing studies that are needed. Patient Selection Prostate Specific Antigen The first reports of targeted focal therapy were small and retrospective, and none set limits on preoperative PSA for study inclusion.10,11 Around this time active surveillance protocols were receiving increased recognition, advocating that men meeting D’Amico criteria for low risk disease (PSA less than 10 ng/ml, Gleason score 6 or less, cT2a or less) strongly
157
be considered for active surveillance.4,12 Given the low likelihood of systemic progression in this group, these patients are ideally suited for focal ablation, and the popularity of this idea is borne out in the selection criteria for ongoing studies (table 1). At the University of Colorado focal therapy is limited to patients with a PSA less than 10 ng/ml, Gleason score 3þ4 or less and a percentage of positive cores on transperineal mapping biopsy of less than 20%.13 Some have argued that given the rarity of biochemical failure, metastasis or death in men with low risk prostate cancer, the urological community should investigate whether focal therapy can also be performed in men with intermediate and high risk disease features.9 Notwithstanding the increased interest in focal ablation, there are several limitations to existing technology that make this option less than ideal. Centers that elect to treat just 1 side of the gland, referred to as hemiablation, often rely on PSA or transrectal biopsy results. Several studies have compared preoperative PSA values to radical prostatectomy specimens in an attempt to ascertain whether PSA values might predict multifocality. Djavan et al found that while there were statistically significant differences in PSA density of the transition zone and the ratio of free-to-total PSA, absolute PSA was not a predictor of unifocal vs multifocal disease.14 A retrospective analysis of 525 radical prostatectomy specimens from the ProtecT trial showed that PSA was not significantly different between patients with unifocal (100) vs multifocal (425) disease.15 The authors concluded that the majority of PSA screen detected cancers (with 10 to 12-core transrectal prostate biopsy) are not amenable to focal therapy given the inability to differentiate among patients based on PSA or extended template transrectal biopsy alone. Tumor Focality Prostate cancer is widely considered a multifocal disease, likely secondary to a genetic field effect that affects the glandular epithelium.16 While unifocality was originally considered necessary to offer focal therapy (hence the initial focus on hemiablation), there has been increasing recognition that targeting the so-called index lesion, defined as the largest focus of cancer, may be sufficient to alter the cancer’s course.17 The basis for this argument comes from numerous histopathological studies examining the relationship of index lesion characteristics (size, grade, extent) to oncologic outcomes, showing that the index lesion is the main determinant of prognosis.18 For example, Hall et al found that the index lesion predicted the clinical course despite the presence of secondary foci in 90% of patients.19 These studies also show that the majority (greater than 80%) of secondary foci do not meet criteria for clinical significance (greater than 0.5 cm3).20 As evidenced by the numbers in the ProtecT trials, only a small number of individuals have unifocal (19% to 23%) or unilateral (18% to 23%) disease at prostatectomy.15,21 We also know, for example, that laterality at radical prostatectomy does not appear to influence the risk of biochemical recurrence, suggesting that bilateral disease is not necessarily worse than unilateral disease. Logically one might
158
Targeted Focal Therapy for Prostate Cancer
Table 1. 3 International, multidisciplinary consensus panels on patient selection criteria and outcome definitions23e25
ITF-FLP (2007) Clinical variables: Clinical stage PSA
IWFTI (International Workshop on Focal Therapy and Imaging) e I (2010)
Less than T2a Less than 10 ng/ml; PSA density less than 0.15 ng/ml/ml; PSA vol less than 2 ng/ml/yr Not mentioned Not mentioned
Not mentioned Greater than 10 yrs
12 or More cores
Transperineal mapping (5 mm grid)
Imaging technique
MRI mentioned before þ after treatment
Histopathology
Gleason 3þ3 or less; 20% or less involvement of any core; 7 mm or less involvement of any core; 33% or fewer pos cores Confined to prostate; lesion 12 mm or less in size; lesion 10 mm or less from capsule
Multiparametric MRI experience increasing but still not generally available Gleason 4þ3 or less
Prostate vol Life expectancy Evaluation þ staging: Biopsy technique
Focality
Further study design: Exclusion criteria
Objectives/end points
Treatment failure definitions
Less than T2a Less than 20 ng/ml
IWFTI e II (2013) Less than T2a Less than 15 ng/ml; greater than 15 ng/ml (with caution); PSA density should not be criterion Any, except HIFU (less than 40 ml) Greater than 10 yrs; age should not be criterion Initial systematic TRUS guided biopsy; MRI/TRUS fusion guided targeted biopsies Multiparametric MRI
Gleason 3þ4 or less; % pos cores should be specified; % core involvement should be specified
Unilateral Ca; no apical or anterior lesions
Confined to prostate
Not mentioned
Not mentioned
Posttreatment mapping biopsy; imaging to characterize treatment effects; urinary, bowel þ sexual morbidity rates; rates of biochemical þ clinical progression þ re-treatment; pt reported quality of life measures Not mentioned
Functional outcome (self-reported questionnaires); oncologic outcome (determined by posttreatment biopsy); need for subsequent treatment
Pts with clinically insignificant disease; previous treatment (surgery, radiotherapy, androgen deprivation therapy); extracapsular extension, seminal vesicle invasion, lymph node or bone metastasis; active UTI Focal ablation of clinically significant disease; neg biopsies at 12 mos
Not mentioned
conclude that bilateral disease should not necessarily preclude the possibility of focal therapy. Studies of secondary foci of cancer have shown that its presence does not appear to impact recurrence rates.22 Indeed if the disease process is driven by the single, predominant lesion, then more men may have the option of focal therapy despite the multifocal nature of prostate cancer. However, there are no data available to our knowledge that confirm that treating only the index lesion will result in long-term success. Two phase II trials are under way that will examine outcomes in patients undergoing targeted focal therapy with secondary, untreated foci of cancer (NCT00987675, NCT00877682). A thorough review of these complex issues regarding the definition of and literature involving multifocality has been published by Karavitakis et al.17
Biochemical failure: unable to define; in-field failure: persistent Ca of same/higher grade or need for re-treatment in same area; selection failure: tumor found after focal therapy in area not originally treated
Multifocality is generally the rule in patients with prostate cancer, and better staging of its location, size and extent is key in determining whether individual patients can be safely offered focal treatment. To date, intraprostatic staging before starting treatment has not been possible. Improvements in imaging and better biopsy strategies are critical to further staging before focal therapy. Practical Criteria for Patient Selection There were 3 international multidisciplinary consensus panels that convened in 2007, 2010 and 2013, and each sought to harmonize definitions of focal therapy and patient selection criteria (table 1).23e25 The criteria from the first panel, the ITF-FLP (International Task Force on Prostate Cancer and the
Targeted Focal Therapy for Prostate Cancer
Focal Lesion Paradigm), were fairly conservative, and the authors note that transperineal mapping biopsy may provide greater accuracy. Transperineal mapping biopsy was listed as a requirement for the 2010 panel but again was omitted by the 2013 panel, instead deferring to MRI-TRUS fusion targeted biopsies. This technique is available only at a few centers, and requires specialized, expensive equipment and a radiologist experienced in evaluating multiparametric MRI of the prostate. However, transperineal mapping biopsy should be easily available to all urologists. Staging and Treatment Biopsy Strategies Most patients considering targeted focal therapy will have had a diagnostic 10 to 12-core transrectal ultrasound guided biopsy. While the majority of these will indicate apparent low risk disease, there can be substantial discordance between these diagnostic biopsies and transperineal mapping biopsies or radical prostatectomy specimens, highlighting their inadequacy as intraprostatic staging tools.26 For example, Beauval et al reviewed 10,785 prostatectomy specimens, of which 919 met the criteria for active surveillance on transrectal biopsy.27 Ultimately 34% were upgraded and only 26% had verifiable insignificant disease on radical prostatectomy, implying that 10 to 12-core biopsies may not adequately assess cancer within the gland. There are several extensive and image guided biopsy techniques that may be used to identify patients for focal therapy. No head-to-head trials have suggested that one technique is better than another, and experience and preference will guide the choice of technique to sample/image the prostate. Appropriate biopsy methods should ideally have several characteristics, including the ability to localize cancerous lesions within the gland, to measure extent of cancer and to accurately determine grade. Transrectal saturation biopsy techniques suffer from a lack of uniform gland coverage, and while there is increased sampling density, repeatable localization is difficult without a template.28 Han et al examined the repeatability and glandular coverage of urologists performing freehand transrectal prostate biopsies on a male pelvic simulation model
159
compared to a robotic arm.29 Urologists tended to under sample a significant portion of the prostate compared to the robot arm. Targeting specific regions varied by 9 mm for humans vs only 1 mm for the robot. Similarly, transperineal biopsy without the use of a localization grid (ie freehand) may improve anterior lesion detection but is likely affected by the same lack of accurate localization and repeatability.30 Transperineal mapping biopsies with a 5 mm grid offer an excellent biopsy based method of staging.31,32 Table 2 shows the results of transperineal mapping biopsy studies to date. Hossack et al performed 414 transperineal or 718 transrectal biopsies before prostatectomy and found the transperineal biopsy detected proportionally more anterior tumors (16.2% vs 12%), identifying them at a smaller size (1.4 vs 2.1 cm3) and stage.33 Our group reported that 180 men with apparent low stage prostate cancer on transrectal biopsy had a substantial rate of upgrading (increase in Gleason score in 27%) and up staging (increase in laterality in 46%) at the transperineal mapping biopsy.34 This further demonstrates the inability of extended template transrectal biopsies to provide adequate data to proceed to focal therapy. In another study the correlation of transperineal mapping in 25 patients to whole mounted radical prostatectomy specimens revealed 64 separate lesions, 25 with clinically significant volumes (mean 1.13 cm3) and 39 with insignificant volumes (mean 0.09 cm3).35 Of the 64 lesions 18 were missed by transperineal mapping biopsy but only 1 was considered significant (Gleason score 8, volume 0.02 cm3). This missed lesion was identified in a patient with another clinically significant lesion that was detected at transperineal mapping biopsy. Transperineal mapping biopsy is performed as a day surgery procedure with the patient under conscious sedation or general anesthesia in the operative suite. Patients receive a dose of prophylactic antibiotics before the procedure. They are placed in the dorsal lithotomy position and local anesthetic is injected into the perineum. A Foley catheter is placed for the duration of the procedure and removed at the end. An ultrasound transducer is placed in the rectum, mounted to accessory equipment for probe stabilization, stepwise linear movement and 3-D image acquisition (BK Medical Flex Focus, Herlev, Denmark). A brachytherapy grid with 5 mm spacing is used as a template. Fiduciary golden markers are placed midway between the apex
Table 2. Results of transperineal mapping biopsy for transrectal biopsy detected unilateral disease or prior negative biopsy for selected studies References
No.
Indication
Median Biopsy Core Count
Bilat Disease/Ca Rate (%)*
Gleason Upgrade 7 or Greater (%)
Active Surveillance Exclusion (%)
Retention Rate (%)y
Onik G: J Clin Oncol 2009; 27: 4321 Barzell WE: J Urol 2012; 188: 762 Taira AV: Prostate Cancer Prostatic Dis 2010; 13: 71 Pal RP: BJU Int 2012; 109: 367 Nafie S: World J Urol 2013; Epub ahead of print Bittner N: J Urol 2013; 190: 509
180 124 373
Unilat disease Unilat disease Prior neg biopsy
50 89.7 55e58
61.1 85 75.9
22.7 Not reported 55.3
69.4 41e80 86.4e91.4
7.7 3 29
40 122
Prior neg biopsy Prior neg biopsy
36 36
41.7 58
41.7 61
71.4 79
485
Prior neg biopsy
59
46.6
57.1
86.7
2.5 5 27
*Bilateral disease applies to studies with an indication of unilateral disease and cancer rate applies to those studying mapping biopsy in setting of prior negative biopsies. y Refers to those patients who required catheter drainage for 24 hours or more.
160
Targeted Focal Therapy for Prostate Cancer
and base on either side of the urethra. These markers allow precision targeting and alignment of specific areas of the prostate during future focal therapy. Transperineal biopsies are obtained at 5 mm intervals using a standard 18-gauge biopsy gun. Deeper (base) vs shallow (apex) passes at the same grid position are performed to ensure complete base to apex gland coverage, and each biopsy is labeled with corresponding xeyez coordinates. Transperineal mapping biopsy as a staging procedure is safe, with multiple studies demonstrating no UTIs, low rates of self-limited hematuria, occasional acute urinary retention requiring temporary urethral catheter (3.7% in one series, 3.2% in our series) and no decrease in quality of life measures.34,36 However, transperineal biopsies are not commonly performed in the United States. They take considerably longer to perform than a transrectal ultrasound guided biopsy, they typically require a general or intravenous anesthetic (although some have successfully adapted the procedure to an office setting), and they are expensive due to operating room and pathology processing costs. Instrumentation for transrectal biopsy was developed more than 25 years ago, while the technology used for transperineal mapping biopsy has been adapted from brachytherapy and cryoablation platforms, making the procedure cumbersome to perform. Imaging Techniques Most centers investigating focal therapy now include 3T multiparametric MRI protocols (including diffusion weighted imaging, dynamic contrast enhancement and spectroscopy to improve on T2 images alone) as part of study parameters before and after focal therapy. The reported sensitivity and specificity vary, but most recent series put both at greater than 85% to 90% with negative regions having a 95% probability of being free of clinically significant cancer.37 Multiparametric MRI has good sensitivity to detect larger high grade lesions, but is more limited for smaller tumors and low grade cancers. Prostate MRI should not be obtained until 6 to 8 weeks after biopsy or treatment given the possibility of bleeding artifact. MRI-TRUS fusion targeted biopsies have recently become possible with groups demonstrating improved sampling of suspicious lesions while perhaps minimizing the overall number of biopsies required to characterize a lesion.38e41 Urologists and interventional radiologists have used the images with the lesions demarcated to perform cognitive registration. Several manufacturers now market a package system in which a localization process (for example, electromagnetic) tracks the position of the probe within the rectum while simultaneously overlaying the MRI and ultrasound images. A biopsy guide allows the operator to target the lesion using a transrectal or transperineal approach. Vourganti et al studied 195 men with negative TRUS biopsy who had 3T endorectal coil MRI.42 Lesions were targeted with MRI-TRUS fusion biopsy. In addition, all patients underwent repeat standard 12-core transrectal ultrasound biopsy. Of the previous negative biopsies 73 (37%) were found to have cancer using the MRI-TRUS fusion biopsy combined with 12-core
transrectal ultrasound biopsy. High grade cancer (Gleason score 8þ) was discovered in 21 men (11%), all of whom had disease detected with MRI-TRUS fusion biopsy. Standard transrectal ultrasound biopsy missed 12 of these high grade cancers (55%). On multivariate analysis only PSA density and MRI suspicion level remained significant predictors of cancer. Availability of all the necessary technology and expertise at various centers of excellence is still fairly limited but is expanding as interest grows. Treatment Modalities To date, most focal therapy trials have focused on cryoablation or HIFU (currently approved for use in Europe but for investigational use only in the United States). Preliminary reports on focal radiotherapy (external beam or brachytherapy) have been published as well.43 Note that patient selection for focal radiotherapy trials is believed to be slightly different than for HIFU or cryotherapy (emphasis on unilateral disease, prostate size less than 60 cm3).44 The American Urological Association recognized cryotherapy for localized prostate cancer as a standard treatment option in 1996. Current devices are labeled third generation, and use urethral warmers, a combination of argon (cooling) and helium (warming) gases, taking advantage of the Joule-Thomson effect, and transrectal ultrasound guidance. At our center we use cryotherapy in patients undergoing targeted focal therapy for prostate cancer. We typically target the index lesion as opposed to hemiablation or hockey stick ablation patterns. With the patient in an exaggerated lithotomy position, the same 5 mm template guide used to perform transperineal mapping biopsies is placed on the perineum. We use the results from transperineal mapping biopsy to plan the areas of the prostate to treat focally (fig. 1). A multifrequency biplanar transrectal ultrasound probe on a stepper is used for visualization of the prostate and surrounding structures. Local anesthesia is administered to the perineum. Temperature monitors are placed near Denonvilliers fascia, the external urinary sphincter or neurovascular bundles to monitor for the
Figure 1. Demonstration of transperineal mapping biopsy results plotted into 3-D planning software used before targeted focal therapy.
Targeted Focal Therapy for Prostate Cancer
161
depicts a cross section of the actual kill zone (corresponding to the target temperature of 40C) and the visible affected zone on ultrasound for modern (1.47 mm, 17 gauge) probes in a 1-probe and 3-probe setup. Targeted focal interstitial laser ablation guided by MRI thermal imaging has been reported and we are in the process of publishing our experience with 9 patients.45 The target coordinates are ablated and monitored using fusion of real-time MRI and ultrasound imaging. This is done as a day surgery procedure and allows for precise ablation of the cancer foci. Thus, this technique has even less potential for collateral damage than cryotherapy.
Focal Therapy Outcomes The 2 original focal therapy series by Onik46 and Bahn47 et al have since reported longer followup but these studies suffer from a lack of standardized or comprehensive patient selection criteria and a retrospective nature. Phase I and II studies have been reported demonstrating safety and adequate efficacy (table 3). Ahmed et al reported on 42 men, age 45 to 80 years, who underwent HIFU for unifocal and multifocal prostate cancer identified on transperineal mapping biopsy and/or multiparametric MRI, with the primary end points of adverse events, urinary symptoms and erectile function.48 One man was admitted to the hospital with acute urinary retention, another had urethral stricture, 9 (22%) had self-limited dysuria, 14 (34%) had debris in the urine and 7 (17%) had UTI. Of 35 men with adequate baseline erectile function (89%, 95% CI 73e97) 31 had erections sufficient for penetration 12 months after targeted focal therapy. Overall 40 patients were pad-free at baseline and were able to return to a pad-free state by 3 months. No evidence of disease was found in 39 of 41 patients on MRI at 12 months, with 4 having undergone a repeat focal therapy session. One man died of pneumonia (3 months after treatment, considered unrelated) and was excluded from the analysis.
Figure 2. Single probe setup (A) and 3-probe setup (B). Note that zone that reaches kill temperature is about 4 mm smaller on each side than visibly affected area. Illustration by Kyle Rove, adapted from data by Oncura, Inc.
appropriate level of freezing and to avoid thermal damage to these sensitive structures (the temperature should remain greater than 15C), even if our intended target is not adjacent to these structures. Cryoneedles are inserted under ultrasound visualization in the area of concern as highlighted by focal planning software that coordinates positive mapping biopsy location, grade and size with the previously registered ultrasound images. Appropriate registration (alignment) is performed using the previously placed fiducial markers. Flexible cystoscopy is performed to visualize the urethra and bladder for needles or thermocouples so that they can be moved before starting the freezing cycles. Lastly, a urethral warmer is placed under cystoscopic guidance. Freezing is performed in an anterior-toposterior direction (if more than 1 probe is used, to maintain visibility) down to 40C for 2 freeze-thaw cycles. Figure 2 Table 3. Results of select focal therapy trials
References
No. Treatment
Nguyen PL: J Urol 318 MRI brachytherapy 2012; 188: 1151 Eisenberg ML: Urology 19 Cryoablation 2008; 72: 1315 Truesdale MD: Cancer J 77 Cryoablation 2010; 16: 544 de Castro Abreu AL: J 25 Salvage cryoablation Endourol 2011; 26: A208 Bahn et al47 25 Cryoablation Ellis DS: Urology 2007; 70: 9 60 Cryoablation Onik G: Urology 2007; 70: 16 55 Cryoablation Ahmed HU: Cancer 39 HIFU 2012; 118: 4148 El Fegoun AB: Int Braz 100 HIFU J Urol 2011; 37: 213
Focal Zone
Biochemical Mos Disease-Free Residual Followup Survival (%) Disease (%)
Urinary Incontinence Erectile (%) Function (%) Fistula (%)
Periphery
62
78
Not reported Not reported Not reported
Not reported
Hemiablation
18
79
10
5.2
Not reported
0
Hemiablation
24
80
40
0
Not reported
Not reported
Hemiablation
31
54
8
5
95
0
Hemiablation Hockey stick Focal Hemiablation
70 12 42 17
92.9 80 95 49
4 40 13 44
0 0 4 5
88.8 70.6 85 95
0 0 Not reported 0
8
0
Not reported
Not reported
Hemiablation 126
38
162
Targeted Focal Therapy for Prostate Cancer
One of the more stringent studies currently under way aims to enroll 140 men with transperineal mapping biopsies before and after focal therapy with HIFU combined with quality of life measures.49 The primary outcome in this study is the absence of clinically significant disease on repeat mapping biopsy. Most studies use 10 to 12-core transrectal biopsies or multiparametric MRI at 1 year to monitor disease status. While PSA is closely followed in studies, there are no agreed-upon definitions of biochemical failure given that viable prostate tissue remains after focal therapy. With regard to following PSA after targeted focal therapy, the magnitude of decrease in PSA after focal ablation will depend on the amount of tissue ablated relative to the remaining prostate. Ideally a stable nadir will be achieved. Figure 3 depicts a flow chart of how to select appropriate candidates for focal therapy, and suggests subsequent followup and disease monitoring. Ongoing trials have begun to differentiate among in-field failures (at site of treatment), patient selection failures (clinically significant cancer found outside the treatment area that was previously missed) and the need for repeat treatment. Particular emphasis is also placed on quality of life measures
(urinary, erectile function, anxiety). As shown in the systematic review by Valerio et al,50 we are on the cusp of multiple, prospectively designed trials that are now coming to fruition. New Directions While the current instrumentation for transperineal mapping biopsy yields superior results compared to transrectal biopsy, it is by no means as accurate as it could be. The biopsy needle used was developed more than 30 years ago for transrectal application. A needle designed to take 1 core from apex to base is needed to fully take advantage of the accurate localization potential of the transperineal biopsy approach. Updated 3-D software is required to record the exact position of each biopsy site so the clinician will have an accurate location of the positive sites when applying focal ablation. Lastly, it will no longer be adequate to put a longer specimen on a piece of TelfaÒ and place it in formalin. A pathology receptacle device is required that maintains the integrity of the core so pathology reporting is also accurate.
Figure 3. Clinical pathway for selecting, treating and following appropriate patients with prostate cancer for targeted focal therapy
Targeted Focal Therapy for Prostate Cancer
Conclusions Phase I and II studies of targeted focal therapy for prostate cancer have demonstrated safety and efficacy. With improved imaging, new MRI-TRUS fusion targeted biopsies and standardized patient selection criteria, phase III study is under way, perhaps setting the stage for a new era of prostate cancer therapy for many individuals. References 1. Bangma CH, Roemeling S and Schröder FH: Overdiagnosis and overtreatment of early detected prostate cancer. World J Urol 2007; 25: 3. 2. Moyer VA: Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2012; 157: 120. 3. Carter HB, Albertsen PC, Barry MJ et al: Early Detection of Prostate Cancer: AUA Guideline. Available at www.auanet.org/common/pdf/education/ clinical-guidance/Prostate-Cancer-Detection.pdf. Accessed April 2, 2014. 4. Dall’Era MA, Albertsen PC, Bangma C et al: Active surveillance for prostate cancer: a systematic review of the literature. Eur Urol 2012; 62: 976. 5. Klotz L: Active surveillance, quality of life, and cancer-related anxiety. Eur Urol 2013; 64: 37. 6. Cooperberg M, Broering J and Carroll PR: Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol 2010; 28: 1117. 7. Nam RK, Cheung P, Herschorn S et al: Incidence of complications other than urinary incontinence or erectile dysfunction after radical prostatectomy or radiotherapy for prostate cancer: a population-based cohort study. Lancet Oncol 2014; 15: 223. 8. Wilt TJ, Brawer MK, Jones KM et al: Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012; 367: 203. 9. Ward JF, Rewcastle JC, Ukimura O et al: Focal therapy for the treatment of localized prostate cancer: a potential therapeutic paradigm shift awaiting better imaging. Curr Opin Urol 2012; 22: 104. 10. Onik G, Narayan P, Vaughan D et al: Focal “nerve-sparing” cryosurgery for treatment of primary prostate cancer: a new approach to preserving potency. Urology 2002; 60: 109. 11. Bahn DK, Silverman P, Lee F et al: Focal prostate cryoablation: initial results show cancer control and potency preservation. J Endourol 2006; 20: 688. 12. Klotz L: Active surveillance with selective delayed intervention: using natural history to guide treatment in good risk prostate cancer. J Urol, suppl., 2004; 172: S48. 13. Barqawi AB, Stoimenova D, Krughoff K et al: Targeted focal therapy in the management of organ confined prostate cancer. J Urol 2014; Epub ahead of print. 14. Djavan B, Susani M, Bursa B et al: Predictability and significance of multifocal prostate cancer in the radical prostatectomy specimen. Tech Urol 1999; 5: 139. 15. Catto JW, Robinson MC, Albertsen PC et al: Suitability of PSA-detected localised prostate cancers for focal therapy: experience from the ProtecT study. Br J Cancer 2011; 105: 931. 16. Jones TD, Wang M, Eble JN et al: Molecular evidence supporting field effect in urothelial carcinogenesis. Clin Cancer Res 2005; 11: 6512. 17. Karavitakis M, Ahmed HU, Abel PD et al: Tumor focality in prostate cancer: implications for focal therapy. Nat Rev Clin Oncol 2010; 8: 48. 18. Wise AM, Stamey TA, McNeal JE et al: Morphologic and clinical significance of multifocal prostate cancers in radical prostatectomy specimens. Urology 2002; 60: 264. 19. Hall GS, Kramer CE and Epstein JI: Evaluation of radical prostatectomy specimens: a comparative analysis of sampling methods. Am J Surg Pathol 1992; 16: 315. 20. Villers A, McNeal JE, Freiha FS et al: Multiple cancers in the prostate. Morphologic features of clinically recognized versus incidental tumors. Cancer 1992; 70: 2313.
163
21. Iczkowski KA, Hossain D, Torkko KC et al: Preoperative prediction of unifocal, unilateral, margin-negative, and small volume prostate cancer. Urology 2008; 71: 1166. 22. Noguchi M, Stamey TA, McNeal JE et al: Prognostic factors for multifocal prostate cancer in radical prostatectomy specimens: lack of significance of secondary cancers. J Urol 2003; 170: 459. 23. Eggener SE, Scardino PT, Carroll PR et al: Focal therapy for localized prostate cancer: a critical appraisal of rationale and modalities. J Urol 2007; 178: 2260. 24. de la Rosette J, Ahmed H, Barentsz J et al: Focal therapy in prostate cancerereport from a consensus panel. J Endourol 2010; 24: 775. 25. van den Bos W, Muller BG, Ahmed H et al: Focal therapy in prostate cancer: international multidisciplinary consensus on trial design. Eur Urol 2014; 65: 1078. 26. Sinnott M, Falzarano SM, Hernandez AV et al: Discrepancy in prostate cancer localization between biopsy and prostatectomy specimens in patients with unilateral positive biopsy: implications for focal therapy. Prostate 2011; 72: 1179. 27. Beauval JB, Ploussard G, Soulié M et al: Pathologic findings in radical prostatectomy specimens from patients eligible for active surveillance with highly selective criteria: a multicenter study. Urology 2012; 80: 656. 28. Falzarano SM, Zhou M, Hernandez AV et al: Can saturation biopsy predict prostate cancer localization in radical prostatectomy specimens: a correlative study and implications for focal therapy. Urology 2010; 76: 682. 29. Han M, Chang D, Kim C et al: Geometric evaluation of systematic transrectal ultrasound guided prostate biopsy. J Urol 2012; 188: 2404. 30. Novara G, Boscolo Berto R, Lamon C et al: Detection rate and factors predictive the presence of prostate cancer in patients undergoing ultrasonography-guided transperineal saturation biopsies of the prostate. BJU Int 2010; 105: 1242. 31. Barzell WE, Whitmore WF III and Andriole G: Transperineal template guided saturation biopsy of the prostate: rationale, indications and technique. Urol Times 2003; 32: 41. 32. Barzell W and Melamed M: Appropriate patient selection in the focal treatment of prostate cancer: the role of transperineal 3-dimensional pathologic mapping of the prostateda 4-year experience. Urology, suppl., 2007; 70: S27. 33. Hossack T, Patel MI, Huo A et al: Location and pathological characteristics of cancers in radical prostatectomy specimens identified by transperineal biopsy compared to transrectal biopsy. J Urol 2012; 188: 781. 34. Barqawi AB, Rove KO, Gholizadeh S et al: The role of 3-dimensional mapping biopsy in decision making for treatment of apparent early stage prostate cancer. J Urol 2011; 186: 80. 35. Crawford ED, Rove KO, Barqawi AB et al: Clinical-pathologic correlation between transperineal mapping biopsies of the prostate and threedimensional reconstruction of prostatectomy specimens. Prostate 2013; 73: 778. 36. Losa A, Gadda GM, Lazzeri M et al: Complications and quality of life after template-assisted transperineal prostate biopsy in patients eligible for focal therapy. Urology 2013; 81: 1291. 37. Villers A, Lemaitre L, Haffner J et al: Current status of MRI for the diagnosis, staging and prognosis of prostate cancer: implications for focal therapy and active surveillance. Curr Opin Urol 2009; 19: 274. 38. Ouzzane A, Puech P, Lemaitre L et al: Combined multiparametric MRI and targeted biopsies improve anterior prostate cancer detection, staging, and grading. Urology 2011; 78: 1356. 39. Pinto PA, Chung PH, Rastinehad AR et al: Magnetic resonance imaging/ ultrasound fusion guided prostate biopsy improves cancer detection following transrectal ultrasound biopsy and correlates with multiparametric magnetic resonance imaging. J Urol 2011; 186: 1281. 40. Kuru TH, Roethke MC, Seidenader J et al: Critical evaluation of magnetic resonance imaging targeted, transrectal ultrasound guided transperineal fusion biopsy for detection of prostate cancer. J Urol 2013; 190: 1380. 41. Walton Diaz A, Hoang AN, Turkbey B et al: Can magnetic resonanceultrasound fusion biopsy improve cancer detection in enlarged prostates? J Urol 2013; 190: 2020. 42. Vourganti S, Rastinehad A, Yerram NK et al: Multiparametric magnetic resonance imaging and ultrasound fusion biopsy detect prostate cancer in
164
43. 44.
45.
46.
Targeted Focal Therapy for Prostate Cancer
patients with prior negative transrectal ultrasound biopsies. J Urol 2012; 188: 2152. Cosset JM, Cathelineau X, Wakil G et al: Focal brachytherapy for selected low-risk prostate cancers: a pilot study. Brachytherapy 2013; 12: 331. Langley S, Ahmed HU, Qaisieh Al B et al: Report of a consensus meeting on focal low dose rate brachytherapy for prostate cancer. BJU Int 2012; 109: 7. Raz O, Haider MA, Davidson SR et al: Real-time magnetic resonance imaging-guided focal laser therapy in patients with low-risk prostate cancer. Eur Urol 2010; 58: 173. Onik GM, Vaughan D, Lotenfoe R et al: The “male lumpectomy”: focal therapy for prostate cancer using cryoablation results in 48 patients with at least 2-year follow-up. Urol Oncol 2008; 26: 500.
47. Bahn D, de Castro Abreu AL, Gill IS et al: Focal cryotherapy for clinically unilateral, low-intermediate risk prostate cancer in 73 men with a median follow-up of 3.7 years. Eur Urol 2012; 62: 55. 48. Ahmed HU, Hindley RG, Dickinson L et al: Focal therapy for localised unifocal and multifocal prostate cancer: a prospective development study. Lancet Oncol 2012; 13: 622. 49. Dickinson L, Ahmed HU, Kirkham AP et al: A multi-centre prospective development study evaluating focal therapy using high intensity focused ultrasound for localised prostate cancer: the INDEX study. Contemp Clin Trials 2013; 36: 68. 50. Valerio M, Ahmed HU, Emberton M et al: The role of focal therapy in the management of localised prostate cancer: a systematic review. Eur Urol 2013; Epub ahead of print.
Editorial Commentary Remember when we used to argue about whether radical surgery was better than external beam radiation for prostate cancer? The consensus back then was that regardless of your bias, whole gland treatment was still needed. This article by Crawford et al is one of many that I am sure will sprout up in the next few years presenting data that focal therapy of the prostate is a reasonable option for many men with early stage disease. As others have shown, low risk prostate cancer is diagnosed in about half of the men undergoing screening.1 The concern with focal therapy, as indicated in this article, is that nearly 30% of men with presumed low risk disease harbor high grade cancer that is unrepresented on the biopsy. With the ability of genomics2 and new age multiparametric MRI scanning,3 clinicians may be able to be more precise about patient selection and evaluation for focal therapy strategies. However, there will still be a subset of men who will be under treated and at risk for relapse. What is not currently known is the salvage rate in these men, and if we are burning any bridges (or freezing any tunnels) by using focal therapy as an initial approach. Having performed many focal cryoablations during the last decade, it is clear to me that this therapy has a definite role in eradicating cancer and preserving function. I continue
to see these men many years after therapy without the need for traditional surgery or radiation. Crawford et al have provided a valuable review of the data in phase I and II studies and of the consensus statements. The optimal therapy for these patients is still unknown and debate will continue as to which approach is best or if any treatment is needed at all. Aaron E. Katz Department of Urology Winthrop University Hospital and Stony Brook School of Medicine Garden City, New York References 1. Klotz L and Emberton M: Management of low risk prostate cancer-active surveillance and focal therapy. Nat Rev Clin Oncol 2014; 11: 324. 2. Fraser M, Berlin A, Bristow RG et al: Genomic, pathological, and clinical heterogeneity as drivers of personalized medicine in prostate cancer. Urol Oncol 2014; Epub ahead of print. 3. Anderson ES, Margolis DJ, Mesko S et al: Multiparametric MRI identifies and stratifies prostate cancer lesions: implications for targeting intraprostatic targets. Brachytherapy 2014; 13: 292.
Reply by Authors In addition to genomics and multiparametric MRI, we also believe precise prostate mapping by biopsy will greatly improve identification and targeting of small regions within
the prostate. Individually or in combination, these new modalities will alter the surveillance and treatment landscape.