Our failures as healthcare providers frequently highlight the opportunities before us. Since the early 1990s, we have been able to increase the detection of prostate cancer while simultaneously reducing the numbers of prostate cancer deaths . However, in the process we have also increased disease treatment-associated morbidity, namely, erectile dysfunction and incontinence, despite rather substantial treatment advances [2–4]. Additionally, mortality from prostate cancer remains common as 29 430 men are estimated to die from prostate cancer in 2018 in the United States . With the US Preventive Service Task Force's temporary stance against prostate specific antigen (PSA) testing (which has now been partially retracted) attention to the morbidity of prostate cancer treatment has been a focus of critique, as well as spurred technological development .
In the 1990s, the general ethos among urologists was that with refinements of surgical techniques, erectile dysfunction and incontinence from prostate surgery could be largely reduced . In the 2000s, with improvements of instrumentation and visualization associated with adoption of robotic surgery, further improvements were expected. In fact, some improvements were made as 12 month continence rates in some series have reached as high as 96% (69–96%) and 12 month potency rates have increased from 26–50% with open retropubic radical prostatectomy to 55–81% with robotic-assisted laparoscopic prostatectomy [3,7–12]. Prostate radiotherapy demonstrates similar incontinence and impotence rates, with the added sequelae of increased bladder cancer risk, rectal bleeding, bowel dysfunction, and urethral stricture disease . Predictability of these complications are far too uncertain and still too frequent for the individual patient . Understandably, with the improvements in prostate cancer imaging and the treatment morbidity associated with whole gland treatment, the medical community began to explore focal treatment options with hopes of avoiding injury to the neurovascular bundle and urinary continence mechanisms.
Although one of the earliest reports of focal therapy for prostate cancer was published in 2002 , mainstream popularization of focal treatment of prostate cancer was dependent on the development of multiparametric MRI, which allowed for tumor localization and biopsy guidance [15–17]. Once a lesion could be reproducibly visualized on imaging, targeting for destruction of localized lesions in the prostate became increasingly feasible. Multiparametric MRI, however, can be unreliable in detecting prostate cancer [17,18], particularly lower Gleason score disease , and underestimates the size of prostate cancer lesions . These imaging limitations can translate into incomplete ablation of identified lesions and cancers missed by imaging and/or systematic biopsy . Furthermore, prostate cancer is a largely multifocal disease creating questions of how many prostate lesions can be safely ablated . Similarly at this time, there is no consensus on whether Gleason ≥8 lesions are even candidates for focal therapy. Based on these limitations, one study espoused that only 38.5% of patients are possible candidates for focal therapy .
HIGH-INTENSITY FOCUSED ULTRASOUND
Despite the limitations noted above, the enthusiasm to explore focal therapy has been strong. High-intensity focused ultrasound (HIFU) is among the most popularly adopted focal therapies. Prostate HIFU uses transrectally delivered focal ultrasound to the prostate to induce coagulative necrosis . As energy is delivered transrectally, the rectal mucosa is often actively cooled to prevent rectal injury and urinary fistula. Given no portion of the device penetrates tissues, HIFU is the only truly noninvasive commercially available focal therapy modality for prostate cancer as other modalities require transrectal or percutaneous probe placement. Most commercially available HIFU platforms are limited to ∼4 cm depth of tissue ablation making treatment of anterior lesions more complicated or impossible . In addition to focused ultrasound, there is also a transurethral nonfocused ablative ultrasound with MRI thermometry under experimental evaluation for focal therapy. Given the paucity of clinical data for the treatment of focal prostate cancer, this review will focus on HIFU only.
The results of the largest focal HIFU trial to date were published in June 2018 [25▪▪]. Guillaumier et al. treated 625 prostate cancer patients with HIFU and reported their 5-year follow-up data [25▪▪]. Eighty three percent of patients had low risk (Gleason 3 + 3 = 6 and 3 + 4 = 7), 14% Gleason 4 + 3 = 7, and 2% Gleason ≥8 disease, respectively. All 625 patients received primary HIFU treatment and 19% (n = 121) required at least two retreatments. Of these only 35% (n = 29) of patients underwent posttreatment rebiopsy, which demonstrated a 14% rate of recurrence within the treatment field, also known as infield recurrence. Failure-free survival, defined as avoidance of the need for radical or systemic therapy, was 88% at 5-year follow-up and metastasis-free survival was 95% at 5 years. In total, 97% of patients did not require urinary absorptive pads at 1–2 year posttreatment, urinary tract infections occurred in 8.5% (53/625), and rectourethral fistulas were rare (n = 2/625) [25▪▪]. These results have been largely mirrored by smaller prior studies [26▪,27,28]. Among five studies, 171 patients were treated as part of published study protocols. In-field recurrences were detected in 0–21% of patients . Incontinence rates were less than 1%, erectile dysfunction rates ranged from 0–25%, and urinary retention occurred in up to 5% of patients .
Advances in HIFU technology have led to technical improvements in prostate cancer ablation ; however even with state-of the art systems, significant shortcomings remain. This was seen in a 2018 report by Hardenberg et al. of 24 patients treated with a recently updated HIFU platform. Nineteen patients had MRI-visible lesions (Prostate Imaging Reporting and Data System 3–5) and five had lesions undetectable by MRI. Patients underwent focal or regional HIFU, with 12 month postoperative biopsy demonstrating persistence of cancer in 8 of 20 patients (40%) . Although many of these treatment failures represent Gleason 6 disease, ultimately 20% of the patients in this study proceeded to prostatectomy at 1-year follow-up. No patient developed urinary complications, however, there was a mild 2 point reduction in average erectile function as measured by the International Index of Erectile Function in preoperatively potent patients at 12 months (confidence interval 15.79–22.21; P = 0.044) . Only one patient experienced greater than grade II Clavien-Dindo complication .
Although the treatment outcomes may demonstrate suboptimal efficacy, the low rates of adverse effects and noninvasive nature of HIFU make it an attractive option among those patients who may have low-volume disease and who want treatment but not definitive whole gland therapy. However, the absence of long-term oncologic follow-up remains a major limitation to satisfactory patient counseling regarding this approach.
FOCAL LASER ABLATION
Although HIFU has garnered favor in clinical use because of its noninvasive marketing label, relative ease of use, and availability of commercial platforms, there are some advantages to the competing therapy of focal laser ablation (FLA) in the treatment of prostate cancer. FLA requires placement of a laser fiber directly into the cancer lesion through a perineal or transrectal puncture. Energy is then transmitted into the lesion creating a volume of thermal necrosis . Although HIFU renders sequential rice-kernel-sized ablations across columns or spheres, FLA creates larger, homogenous circular or elliptical ablation zones around the laser tip. Repeated ellipses of ablation are manually overlaid, creating a sharply demarcated treatment zone . This can be done under local anesthesia, whereas HIFU requires general anesthesia and a transrectal approach. Additionally, unlike HIFU which is limited in its depth of penetration to 4 cm, FLA can conceivably be used to ablate any region of the prostate. FLA provides the added benefits of MRI compatibility, allowing for use of real-time in-bore MRI guidance and thermometry, and the ability to perform it without need for general anesthesia [33,34].
Given the technical difficulties of FLA and the lack of prostate-specific commercially developed FLA targeting, monitoring, or navigation platforms, there are limited data for FLA in treating prostate cancer. In a 2016 published phase II trial, Eggener et al. treated 27 men with a mean PSA of 4.4 and Gleason 6 or 7 disease . At 3 and 12 months, 96% and 89% of patients, respectively, were absent of disease recurrence in the ablation zone (in-field recurrence); however, 37% of patients were found to have some residual cancer at any location within the prostate gland on 12 month systematic 12-core rebiopsy (out-of-field recurrence) . There were no significant changes in urinary symptoms (measured with I-PSS scores) or erectile function [measured by sexual health inventory for men (SHIM) score] at 12-month follow-up. The most common adverse events were hematuria (15%) and urinary retention (8%) . Unfortunately, the majority of the published FLA data is limited to cohorts of less than 30 patients, limiting the conclusions that can be drawn about this treatment modality [31,34–39].
The largest study assessing transrectal FLA is currently ongoing. Interim results were recently reported in 2018 (Feller et al.) on the treatment of 98 patients and 138 tumor foci using real time MRI guidance . They reported 23% rate of in-field cancer recurrence, with no serious adverse events and no statistically significant changes in International Prostate Symptom Score or SHIM scores at 12 months . Currently, there is no long-term oncologic follow-up on the efficacy of FLA, limiting its use to largely clinical trial settings. The limited side-effect profile, excellent precision of ablation obtainable with laser energy delivery and the absence of documented rectal fistula are potential advantages of FLA. Additional navigation and verification software need to be developed to ensure better overlapping treatments and refine the precision and accuracy of this approach for larger planned treatment volumes. MRI–transrectal ultrasound (TRUS) fusion guidance platforms have been developed (at the National Institutes of Health (NIH) and University of California, Los Angeles) for TRUS MRI fusion guidance, but broadly available FLA platforms are not yet available [34,41].
In contrast to heating energy modalities, cryotherapy, initially used for whole gland ablation, has been repurposed for treatment of focal prostate lesions. Through repeating freeze and thaw cycles, cryotherapy induces irreversible cell rupture and apoptosis . As with the other treatment modalities, efficacy of cryotherapy has been quite variable with 2–25% of posttreatment biopsies demonstrating in-field recurrences, 0–31% rates of erectile dysfunction, 1–17% rates of urinary retention and less than 5% rates of urinary incontinence [29,43,44]. Although 12-month erectile function is generally poor , there is some evidence that at long-term follow-up of 4 years erectile dysfunction can match levels of active surveillance controls . Rare urinary fistulas have been reported . Given the historically high rates of erectile dysfunction and fistula associated with whole gland cryoablation, this modality seems to have been associated with a certain stigma which may limit its adoption.
Perhaps the most novel of the contemporary focal therapy techniques is irreversible electroporation (IRE). In IRE, electroneedle probes are placed through the perineum around the ablative target under ultrasound or MRI guidance. High-voltage bursts of electric current are then passed through the probes causing pores to form in prostate cell walls which ultimately result in cell death . Results from one of the largest IRE studies was recently published by van den Bos et al.[48▪] in which 63 patients with Gleason 6–7 disease were treated with IRE. Sixteen percent of patients had an in-treatment field recurrence and 24% were found to have persistent cancer anywhere within the prostate. No high-grade adverse events occurred and physical, mental, bowel, and urinary quality of life measures remained unchanged at 6 months postoperatively. Despite the theoretical claim that IRE might be less damaging to nerve tissue, mild declines in sexual quality of life median score from 66 to 54 at 6 months (P < 0.001) were seen [48▪]. This novel method has yet to be investigated further in larger scaled studies.
Photodynamic therapy (PDT) is among the most well-studied focal therapy modalities in the short/intermediate term. PDT is accomplished through systemic administration of relatively biologically inert drug which can be activated to release a cytotoxic substance when exposed to light. These drugs are commonly referred to as photosensitizers. A phase III randomized controlled trial comparing PDT vs. active surveillance was recently published [49▪▪,50▪▪]. Anesthetized patients in the PDT arm were given a systemic photosensitizer (padeliporfin) intravenously, which was then activated by infrared light, typically introduced into the prostate via probes placed through the perineum. Activation of the photosensitizer leads to generation of superoxide and hydroxyl free radicals in the infrared-exposed areas, resulting in vascular thrombosis and coagulative necrosis .
In October 2018, Gill et al.[49▪▪] reported a 4-year update of the results from the phase III randomized trial comparing PDT to active surveillance. In total, 413 men with low-risk prostate cancer (Gleason 6 and 7) were randomized to PDT (n = 207) vs. active surveillance (n = 206). At 2 year follow-up, 50% of patients in the treatment arm were still found to have cancer anywhere in the prostate, with 25% having residual cancer within the treatment field [49▪▪]. These rates of in-field recurrences are comparable to those seen in the FLA and HIFU trials [28,35,49▪▪]. Metastasis-free survival was the same in both groups (99% vs. 99%) at four years [49▪▪]. Ultimately, the authors argue that the utility of this treatment is in the reduction of patient progression to radical therapy. The conversion rate to radical therapy was 24% in the PDT group vs. 53% in the active surveillance group (hazard ratio 0.31, 95% confidence interval 0.21–0.46) [49▪▪]. This result, however, was partially confounded by the fact that more patients in the active surveillance arm chose to undergo radical therapy without a clinical indication. Earlier results from the same trial, including complications, were reported by Azzouzi et al.[50▪▪]. Adverse events were more common in the treatment arm with erectile dysfunction rates reaching 38 vs. 11% in the control arm, respectively. Urinary complications of retention or incontinence affected 27 vs. 7%, respectively. Given that all of these patients fell into a low-risk category preoperatively, some authors have questioned if PDT treatment was worth these adverse events . Although PDT is well studied, the outcomes are comparable to other focal therapies. Newer photosensitizers targeting prostate-specific membrane antigen (PSMA) are also being developed, allowing for more targeted and specific release of reactive species in areas expressing PSMA which may theoretically improve disease targeting and treatment outcomes .
Each mode of focal therapy demonstrates some early promise. However, they are all limited by poor navigation, inadequacy of imaging to delineate tumor boundaries, and variable precision of tissue destruction. These shortcomings may explain the high rates of in-treatment field recurrence and the high frequency of cancer detection globally within the prostate gland after treatment. Among well-selected patients, focal therapies demonstrate short-term local disease control (Table 1) with minimal adverse side-effects (Table 2). For certain well-selected patients, the prospect of focal therapy in place of radical surgery or active surveillance may be an attractive alternative, or may be an adjunct to active surveillance . At present, the lack of long-term oncologic outcomes, imaging and navigation shortcomings, and uncertainties about the clinical efficacy of focal treatment for high-grade lesions has led organizations such as the American Urologic Association/American Society for Radiation Oncology/Society of Urologic Oncology, and European Association of Urology to recommend against focal therapy as part of standard of care treatment at this time [29,54]. New guidelines and advancements require evidence-based medicine to better study the long-term results of focal therapy in the setting of clinical trials or registries.
Perhaps with further improvements of imaging modalities and improved targeting of ablation zones, the efficacy of focal treatments will improve. For example, in recent years, novel PET agents that more effectively detect prostate cancer have reached the US commercial market. Platforms such as PSMA PET in combination with MRI fusion provide improved cancer detection, localization, and characterization [55,56]. Additionally, contrast enhanced and superhigh-frequency ultrasound have shown some promise for improved cancer detection [57,58]. It has yet to be seen how integration of these new technologies will affect focal therapy outcomes, but optimism abounds about our future ability to treat well-selected patients with localized prostate cancer with less invasive approaches and less morbidity.
Financial support and sponsorship
NIH and Philips have a Cooperative Research and Development Agreement. NIH has intellectual property in the field, including among other patents and patent applications, Patent: ‘System, methods, and instrumentation for image-guided prostate treatment’ US Patent number: 8948845, with inventors/authors B.W. and P.P. NIH and Philips (InVivo Inc) have a licensing agreement. NIH and authors B.W. and P.P. receive royalties for a licensing agreement with Philips/InVivo Inc. NIH does not endorse or recommend any commercial products, processes, or services. The views and personal opinions of authors expressed herein do not necessarily reflect those of the US Government, nor reflect any official recommendation nor opinion of the NIH nor National Cancer Institute.
Conflicts of interest
There are no conflicts of interest.
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