Focal Ablation Therapy for Prostate Cancer: A Literature Review

: The incidence and mortality of prostate cancer (PCa) are gradually increasing. Traditional treatments for PCa may result numerous side effects and complications that affect patients’ quality of life. Furthermore, older patients frequently cannot tolerate conventional treatments, such as surgery, chemotherapy, and radiotherapy. Thus, minimally invasive and effective therapeutic approaches for PCa need to be developed for clinical practice. Focal ablation therapy, which uses high temperature to destroy tumors, holds promise as one such approach. It has been applied to PCa in several countries with gradual success and clinical practice This review briefly discusses the application of high-intensity focused ultrasound ablation (HIFU), cryoablation, laser ablation (LA), and radiofrequency and microwave ablation (RFA, MWA) for PCa, including the principles of treatment, clinical effects, and complications. The aim of this review is to provide a reliable reference for the application of focal ablation therapy to PCa.


Introduction
The morbidity and mortality of prostate cancer (PCa) are gradually increasing worldwide [1]. With the widespread application of digital rectal examination (DRE), prostate-specific antigen (PSA) test, and transrectal ultrasound (TRUS), PCa is increasingly diagnosed in the early stage. Some of these patients (15%) receiving active surveillance (AS) developed advanced PCa [2]. Traditional treatments, such as surgery, external radiotherapy, and endocrine therapy, can result in numerous side effects [3,4]. Management concerns include a variety of serious challenges, including local recurrence, hormone resistance, and intolerance of operation at an advanced age.
Focal ablation therapy aims to provide the effective oncological benefit of active treatment options while reducing the risk of side effects through preserving noncancerous tissues. Focal ablation therapy, including high-intensity focused ultrasound (HIFU), cryoablation, laser ablation (LA), radiofrequency ablation (RFA), and microwave ablation (MWA), possesses advantages of being minimally invasive and requiring local anesthesia, shorter length of stay in hospital, and fast recovery [5][6][7]. It has been tested in various countries and applied to PCa as well as to other benign and malignant tumors, and proven to be safe and effective. In this review, we aimed to present what is known about the application of focal ablation technologies for PCa and provide a reliable reference for future clinical application.

Principle
HIFU is a noninvasive therapeutic technique, producing ultrasound waves generated by a spherical transducer. The ultrasonic energy is focused on a fixed point, and the temperature at the target point reaches 80-100 °C, resulting in tissue destruction through coagulative necrosis, while preserving adjacent tissues. The process is combined with cavitation, when microbubbles may form in the tissue and implode, causing mechanical damage by disruption of the cell membranes. It is precise for ablating prostate tissues with a sharply demarcated transition between the coagulated zone and the surrounding gland. The coagulated tissue can be gradually absorbed or scarred. The European Association of Urology guideline has recommended HIFU as an alternative therapy for the treatment of PCa [8].

Clinical application
The transrectal HIFU was first reported in the treatment of benign prostatic hyperplasia (BPH) in the 1980s [9]. The application of HIFU in localized PCa was officially reported in 1995 [10]. At present, HIFU can be used as a first-line treatment option for cases with low-to-medium-risk PCa who cannot tolerate traditional treatment [11], and it can also be used as a palliative treatment strategy for patients with advanced drugresistance. Due to the limitation of focal length, the volume of the prostate is generally below 40 ml [12]. Transurethral resection of the prostate (TURP) can be performed before HIFU to reduce the size of the prostate and remove large calcified masses with diameter more than 1 cm.
At present, biopsy is performed after HIFU to evaluate clinical effects. The results of a multi-center trial indicated that the negative rate of biopsy is 55-100% after HIFU treatment. The larger the prostate, the higher the positive biopsy rate for PCa and the higher the Gleason score [13][14][15]. The 5-year disease-free survival (DFS) rate of low-and middle-risk PCa patients after HIFU treatment was reported as high as 77% [16]. The combined PSA values with prostate biopsy are used to monitor recurrence after HIFU. PSA is an androgen-regulated serine protease produced by both prostate epithelial cells and PCa, as well as being the most common serum marker for PCa. Previous research demonstrated that PSA can reach the lowest level (0.4 ng/ ml) after treatment of PCa with HIFU [17]]. It has also been reported that a PSA level of 0.43 ng/ml is critical to predict recurrence after treating PCa with HIFU [18]. In 2017, a number of scholars compared functional and oncologic outcomes of HIFU hemiablation of the prostate with robot-assisted laparoscopic prostatectomy (RALP) in the treatment of unilateral PCa, and found that HIFU hemiablation was comparable to RALP in terms of controlling localized unilateral PCa, with no significant differences in the need for salvage therapies [19].
In recent years, magnetic resonance imaging (MRI)guided HIFU treatment has gradually attracted attention. In 2017, Tay et al. and Ghai et al. reported the utilization of MRI-guided HIFU in the treatment of PCa with lowrisk and small lesions in Europe, and highlighted its safety and effectiveness in short-term follow-up [20,21].

Complications
Common complications after HIFU include transient urine retention, sexual dysfunction, urinary incontinence, rectal burns, urethral fistula, and urethral stricture.
Transient urine retention is generally caused by temporary swelling of the prostate after HIFU, with an incidence of 6-32%. Patients only rarely require longterm indwelling of the urinary catheter or bladder fistula [13][14][15].
The rate of erectile dysfunction is 24-77% after the HIFU. However, with the monitoring of neurovascular bundles during the treatment, this complication has been improved [20,21]. The causes of urinary incontinence include sphincter damage, genital nerve damage, and urethral droop, with an earlier reported incidence of 6-32%. In recent years, with the advance of technologies, the incidence rate of urinary incontinence has gradually decreased to only 1-5% of patients needing intervention [13][14][15]. It has been pointed out that implementation of TURP before HIFU can reduce the incidence of stress urinary incontinence, urethral stricture, and bladder outlet obstruction [22]. The most severe complications are rectal burns and urethral fistula, and the use of rectal cooling devices reduces these complications [23]. Delayed complications of HFIU include primarily urethral stricture (2-17%) [12][13][14][15].

Principle
Cryoablation uses low-temperature freezing and rewarming of thawing to destroy tissues, resulting in irreversible damage to cells in target tissues. When the temperature is lower than zero, crystals appear in the extracellular fluid, high osmotic pressure forms between the inside and outside of cells, and water transfers from the inside to the outside of the cell, leading to cell dehydration and changes in pH value. The fluid is transferred into the cells, causing the cells to burst instantaneously, and at the same time, the vascular dilatation around the tissue leads to increased permeability of the vascular wall, damage to the endothelium, and microthrombi formation [24,25].

Clinical application
Application of cryoablation to the treatment of BPH was first reported in 1966 [26], and use of transperineal cryoablation for PCa was reported in 1972 [27]. Since this method did not fully inactivate tumors [28,29], and a number of complications were observed, so the cryoablation was not widely used in treating in prostate disease. However, this situation has improved as transrectal ultrasound and MRI monitoring the cryoablation process [30].
Cryoablation has gradually been applied more often to prostate diseases with the utilization of Foley's urethral protection of the urethra [31], rectal perfusion of saline [7], and temperature sensors placed on external anal sphincter and neurovascular bundles [32]. The American Urological Association detailed the application of cryoablation in local PCa in 2008 [25]. Cryoablation is generally used for low-risk (T1c-T2a; Gleason score, 6; PSA < 10 ng-/mL) and moderate-risk (Gleason score, 7; PSA, 10-20 ng/mL) groups of patients with PCa. However, patients with lesions near the neurovascular bundle, severe lower urinary tract symptoms, or a prostate volume more than 50 ml are not eligible for cryotherapy. Hormonal therapy can be used to reduce the size of the prostate to achieve indications [33].
There is still no consensus on how to determine tumor recurrence after cryoablation. Due to the PSA released by the necrosis cells after ablation, PSA generally reaches the nadir within 3 months after treatment [33]. In addition, because prostate tissue around the urethra still exists, PSA can still be detected in the serum. Generally, a biopsy is undertaken at 6 and 12 months after cryoablation to detect tumor cells. The literature has reported a positive rate of 7.7-23% [31][32][33][34][35].
Randomized controlled trials (RCTs) have confirmed that long-term survival outcomes are similar for cryoablation and radiotherapy for localized PCa [36]. In 2008, Jones et al. reported follow-up data for cryotherapy for PCa, and pointed out that the survival rate was related to tumor stage [37]. In 2015, Guo et al. studied the use of cryoablation to treat stage T3 PCa patients, and the 5-year overall survival (OS) was 85.3% [38].

Complications
Common complications of cryoablation for PCa include sexual dysfunction, urinary incontinence, urinary retention, urethral stricture, urethral fistula [39], and penile numbness [33]. It has been reported that cryoablation has a more significant influence on sexual function than external radiotherapy; thus, patients who aim to retain sexual function may not be eligible for cryoablation [40]. Urinary incontinence may gradually recover after ablation, and swelling in the penis or scrotum, hydronephrosis, and small bowel obstruction were rarely reported [41]. However, with continuous improvement of medical technology and application of protective measures, complications may be remarkably alleviated.

Principle
LA is the transmission of light into tissues through a 21G Chiba needle quartz fiber with a diameter of 300-600 um. The high temperature in tissues occurs after absorbance of light, and irreversible damage may be observed in tumor cells after exposure to temperatures above 60 °C [42]. The penetration depths in tissues differ according to the wavelength of laser. The infrared penetration is ideal. Diode laser with a wavelength of 800-980 nm and yttrium aluminum garnet (Nd: YAG) laser with a wavelength of 1064 um have a penetration depth of about 10 cm.
The earliest LA was called "bare fiber" [43]. Several efforts were made to elevate the ablation volume by increasing the power while avoiding carbonization of the surrounding tissue, including sapphire tip fiber, fiber end plus laser emitter, and cold cycle [44]. These measures reduce the impact of carbonization on the penetration of light, as well as expanding the scope of ablation [45]. The volume of LA is not only related to the light source and the medium, but also can be affected by the characteristics of tissues, especially tissue perfusion. The high tissue perfusion or surrounding large blood vessels affect the laser heating as a "radiator", because hemoglobin can absorb light, and heat is taken away [46].

Clinical application
Salon et al. first used laser as a surgical tool [47]. In the 1980s, LA was utilized for the treatment of brain and prostate tumors [48,49].
Lindner et al. conducted LA on two batches of patients with PCa. There were 12 cases of PCa in the first batch, and after 6 months of LA, the biopsy showed no tumor in 67% of the target area and no tumor in 50% of the whole glands, and there were no significant complications [50]. In the other batch, the patients underwent PCa resection 1 week after ablation, and the postoperative pathology revealed that the ablation lesions were even coagulation necrosis, with clear borders and surrounding bleeding rings [51].
In 2013, Aytekin et al. used MRI-guided transperineal biopsy for patients with low-risk PCa, and after half a year, 78% (7/9) of tumor cells were faded in the ablation area [52]. The MRI-guided LA for moderate-risk PCa was found safe and feasible in a phase I clinical trial, which was conducted by the University of California, Los Angeles, in 2015 [53]. In the subsequent phase II clinical trial, LA was used to treat low-risk PCa patients (T1c-T2a), and the three-month biopsy negative rate was 96% [54]. With development and advancement of multimodal medical image, the ablation will become more accurate. The fusion images of MRI and ultrasound were employed to guide transrectal LA for patients with moderate-risk PCa. After half a year, the results of biopsy unveiled that 30% of patients were tumor-free, local tumors were found in 30% of patients with Gleason score 6, and 40% had sustained moderate-risk PCa [55].
At present, LA is extensively utilized for the treatment of low-or moderate-risk PCa (PSA < 15 ng/mL; Gleason score, 6-7; clinical-stage, T1c-T2a). Because the maximum ablation area of a single laser is about 2-3 cm in diameter, it may be a risk for LA in some large tumors or tumors adjacent to the critical organs, such as vascular nerve bundles, urethral sphincter, and rectal wall.

Complications
At present, the LA in the clinical treatment of PCa is mainly in phase I-II clinical trials [52][53][54], indicating that it is safe and feasible, while few studies have yet reported complications. The most common complications include hematuria (15%), perineal ecchymosis or abrasion (11%), glans paresthesia (11.1%), acute urinary incontinence (4%), and sexual dysfunction. Among them, hematuria does not need special treatment, and it will gradually disappear after a few days. Sexual dysfunction generally reaches the lowest level during 1-3 months after LA, and it will gradually return to normal after 1 year [52].

Principle
RFA and MWA are currently dominant modalities to treat unresectable liver tumors. The ions and molecules in the tissue oscillate under the current and electromagnetic waves, respectively, and irreversible damage to cells happens under high temperature. The difference is that carbonization occurs when the temperature is extremely high during RFA, which hinders the propagation of RF current and limits the range of ablation. MWA is not affected by current, tissue drying, and carbonization, and a relatively broad range of damage occurs in a short period of time.

Clinical application
When these two ablation technologies were used for PCa via transurethral or rectal puncture [56][57][58], and the results indicated that this method caused damage to the urethra or rectum. Thus, perineal puncture was recently used in the ablation of PCa. Previous research pointed out that the RFA can be used in treating PCa through TRUSguided perineal puncture. At 1 week after ablation, the prostates were obtained by the surgeon, and the pathologist confirmed that all lesions were inactivated. The size of lesions was 2 × 2 × 2 cm. MRI predicted that the lesions were consistent with the pathology [59,60].
In China, Wu et al. [61] and Hu et al. [62] demonstrated the application of RFA to PCa through perineal puncture under CT or ultrasound guidance in 2002, proving that this method does not cause damage to the urethra, does shorten the length of hospital stay, and is safe and effective as well. Additionally, it was uncovered that the distance from the RF electrode to the urethral sphincter near the apex of the prostate should be more than 1 cm to avoid urinary incontinence caused by urethral sphincter damage [61,62].
A pilot study that evaluated the recurrence after RFA for PCa in 2005 showed that in 90% of the patients PSA decreased more 50%; in 72% of the patients PSA reduced by more than 70%; and in 46% of the patients PSA decreased by more than 80%. Besides, the PSA doubling time was remarkably shorter than before the ablation [63]. In China, RFA was used for PCa through perineal puncture under CT or TRUS guidance, highlighting the feasibility of this technique accompanied by excellent clinical outcomes [64][65][66].

Complications
The most common complications of RFA are transient gross hematuria (4.5-19%) and fever. There are also bladder spasms (9%), dysuria (9%), urinary tract irritation (13.6%), and local hematoma (4.5%), and other complications. The above-mentioned conditions returned to normal after RFA within a short period of time [62,63,65,66]. Xu et al. reported a case of rectal bladder fistula after ablation, and the urinary catheter was left for 1 week to observe the hematuria and prevent acute urinary retention.

Conclusions
Each focal ablation technology possesses advantages for treating PCa. Among them, the use of HIFU and cryoablation is relatively mature in different countries. An advantage of HIFU is being non-invasive while cryoablation is minimally noninvasive. However, in order to use HIFU and cryoablation technologies, the diameter of the tumor must be less than 4 cm and the volume of the prostate must be less than 40 mml. In addition, these methods are time-consuming (1-3 h). The diameter of the cryoablation probe is relatively large. During the ablation process, the urethra needs to be heated to prevent urethral damage and the cryoablation probe needs to be more than 1 cm away from the urethra to prevent urethral damage. The operation time is relatively short and can be performed with local anesthesia in outpatient clinics. However, there is currently no right way to monitor the precise range of ablation. In summary, focal ablation therapy should be individualized according to the location, size, and the number of tumors. Recently, Liu et al promise that the appropriate ablation technology can be selected for PCa patients according the shape and volume of ablated lesions through animal experiment results [67].
Focal ablation therapy is currently applied to localized PCa (PSA < 15 ng/mL; T2a; Gleason score, 3 + 3 or 3 + 4) [11,68]. The concept of "Index Lesion" provides a theoretical basis for the focal ablation therapy of PCa. "Index Lesion" refers to the main lesions in PCa causing disease development, with a volume greater than 0.5 ml or the Gleason score greater than 6 [69,70]. Hence, a number of scholars have demonstrated that ablation for index lesion will degrade other tumors. Multi-parametric MRI (mp-MRI) can show 92% of the index lesions [71]. Recently, the fusion image of mp-MRI and TRUS was used to guide the ablation of PCa [72], combining the advantages of these two medical imaging technologies. The lesions displayed in the MRI and the process of puncture and ablation can be dynamically observed under TRUS.
Focal ablation offers a promising outlook for the future in the treatment of PCa, with the goal of effectively achieving cancer control while minimizing morbidity. Additionally, it is critically important that good prospective randominzed clinical trials for each ablation technology be performed to assess the advantage of each treatment modality and to determine long-term efficacy.