Review Article | Open Access
Research Progress in Focal Treatment of Prostate CancerSongtao Cheng1, Shize Wang1, Jing Liu1, Jianlin Huang1, Jiannan Liu1
1Department of Urology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, China.
Correspondence: Jiannan Liu (Department of Urology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Chengdu, China, 610072, China; Email: firstname.lastname@example.org).
Annals of Urologic Oncology 2023, 6(2): 79-86. https://doi.org/10.32948/auo.2023.06.24
Key words prostate cancer, focal treatment, high intensity focused ultrasound, focal laser ablation, cryotherapy
High intensity focused ultrasound (HIFU) is one of the most commonly used focal treatment modalities. The ultrasound probe is placed in the rectum at the beginning of the procedure. The prostate volume is measured, and an image is created. The doctor marks the treated area on the image. Through HIFU, precise, concentrated ultrasound waves are delivered to the target tissue. Within 2-3s, the temperature of the tissue can be raised to nearly 100 °C and coagulate necrosis can occur . Guillaumier et al.  conducted a study, which included the largest clinical trial of HIFU for prostate cancer to date, involving 625 patients with non-metastatic prostate cancer. The 5-year failure-free and overall survival rates for the entire patient cohort were 88% and 99%, respectively. Ganzer et al.  followed up 538 patients with local prostate cancer treated with HIFU alone in a single center for nearly 10 years. According to the statistics, the 5-year and 10-year biochemical disease-free survival rates were 81% and 61%, respectively, and the 10-year tumor-specific survival rates were as high as 94% to 97%. In another study, de Castro Abreu et al.  followed up 7 patients who underwent HIFU semi-glandular ablation by enhanced transrectal contrast ultrasound (TRUS). The median follow-up after HIFU was 15 (13-20) months, and the prostate volume decreased by 32.5% (range 0-74%), 82% reduction in PSA levels (range 30% to 95%). The median duration of PSA decline was 3 months (range 2 to 12 months). Nahar et al.  conducted a study that included a total of 52 patients, and 17% (5/30) of the patients had positive biopsy results 12 months after surgery. After 5 months, Ghai et al.  found that residual prostate cancer was detected in 7% (3/44) of the patients at the treatment site. In addition, Albisinni et al.  found no statistical difference in the probability of requiring further treatment due to disease progression after HIFU versus RP. These studies all confirmed that HIFU can achieve better tumor control outcomes in the focal treatment of prostate cancer. At the same time, HIFU also has obvious advantages in terms of safety as Guillaumier et al.  confirmed that 98% (241/247) of patients achieved complete pad free urine control; Nahar et al.  also found that the urinary system function of the patients recovered to the baseline level in 3-6 months, and the sexual function recovered in 12 months. Ghai et al.  proposed that the median international index of erectile function at 5 months after surgery, IIEF and international prostate symptom score (IPSS) have no significant differences with baseline prostate symptom score. HIFU has a good treatment success rate, and the safety is guaranteed. At the same time, the operation can be carried out under spinal anesthesia or intravenous anesthesia without incision on the skin, and the patients recover quickly after surgery . However, in Guillaumier et al.  found that patient follow-up was insufficient, with only 222 patients receiving puncture biopsy after treatment, and the results obtained were not reliable enough. Therefore, clinical studies with large samples and long-term follow-up are still needed to observe the therapeutic effect of HIFU.
Focal laser ablation
Focal laser ablation (FLA) is treated by inserting a small laser fiber, which is through the perineum or rectum into the tumor and using its discharge to heat up rapidly, causing coagulation necrosis in the controlled area, thereby reducing the risk of damage to adjacent structures . The number of clinical studies on FLA is small, and most of them are small samples. Walser et al.  conducted a study, including 120 patients with low - and medium-risk prostate cancer, 17% (20/120) of whitch received further treatment for recurrence after 1 year of rectal FLA treatment . Alhakeem et al.  also reached a similar conclusion, with 20.4% (10/49) of patients still having tumors in the treated area after treatment. However, there were some evidence,which were from the United States authoritative Surveillance, Epidemiology, and End Results (SEER) database, showing that the difference in cancer specific mortality (CSM) between FLA and RP is not statistically significant  , while RT had a significant advantage in survival benefit . The advantages of FLA were mainly reflected in effectiveness and safety: most patients had no significant differences in IPSS, sexual health inventory in men (SHIM) scores. Besides that, some patients would return to baseline over time even if affected . In addition, FLA can be performed under local anesthesia with less surgical risk.On the one hand, its disadvantages are reflected in the higher requirements for clinicians in terms of technology  , on the other hand, there is still a lack of long-term follow-up data.
Cryotherapy mainly involves quick freezing, slow thawing, and a repetition of the freeze-thaw cycle. There are two main mechanisms by which cryotherapy destroys tissue: one is cell damage from the cooling and heating cycles; The other is progressive failure of tissue microcirculation and blood vessel stasis. The temperature of frozen tissue should reach -50 ° C for tumor treatment, but there is no consensus on the optimal duration of freezing . Chuang et al.  performed negative biopsies on 61 patients who underwent half-side cryotherapy (22/27). Tan et al.  used fractional cryoablation, which had 1-5-year fail-free survival rates of 98%, 89%, 84%, 75%, and 75%, respectively. By risk stratification, Mercader et al.  found that biochemical progression-free survival rates were 70.2%, 70.3% and 50% in the low, medium and high risk groups, respectively. However, their study used neoadjuvant therapy for 3 months for 5-year treatment, failure free survival rates of 85% ,meanwhile biochemical failure free survival rates of 62% in patients with larger prostate volume . In addition, there was much data, which was from SEER, reflecting that the 10-year tumor-specific survival rates for cryopreservation and surgery were 98.1% and 99.2%, respectively . Freezing was also associated with better outcomes. Besides that, the above studies also analyzed the safety, 95% to 100% of patients can maintain pad free urine control after surgery [36-38]. Shah et al.  detected that the probability of IPSS and IIEF scores returning to baseline 12 months after surgery was 78% and 85%, respectively. Through the above analysis, it can be found that cryotherapy has a good oncologic outcome, but the standardized treatment procedures still need to be further explored. Some studies suggest that 3D mapping biopsy, which is before cryotherapy for prostate cancer, can better stratify patients' risk and reduce the failure rate of treatment . At the same time, cryoablation has a certain impact on function, and more exploration is needed in the subsequent use.
The increase in membrane permeability,that results from the application of a pulsed electric field, is known as electroporation. Electroporation can be reversible or irreversible, depending on different current parameters and cell characteristics. The principle of irreversible electroporation (IRE) stems from it . IRE causes cell death by forming nanopores inside the cell membrane without causing thermal effects. There are some advantages of IRE, for example, it does not affect the therapeutic efficacy through energy dissipation due to heat loss . A preclinical study in dogs showed that collagen structures such as blood vessels and nerves were not damaged after IRE treatment . If this discovery is confirmed, it could encourage the wider use of IRE. Blazevski et al.  conducted a clinical trial including 123 patients, with a 3-year failure-free survival rate of 96.75% and a metastasis-free survival rate of 99%. Collettini et al.  found that the recurrence rate after 6 months was 17.9% (5/28). In addition, IRE for apex ablation of the prostate also achieved a surprising outcome, with a failure-free survival rate of 90% (36/40) after follow-up of more than 3 years . Within 1 year after IRE, the overall urinary control function of patients was almost back to baseline level, and even 76% to 94% of patients maintained erectile function after surgery [45-47]. IRE has a good oncologic outcome and a low complication rate after treatment. Because it may be selective and can preserve blood vessels, nerves and other tissues, IRE has broad application prospects. The defects of IRE are mainly manifested in the need for general anesthesia and evaluation during treatment  , and may lead to arrhythmia in patients during treatment. Nevertheless, synchronizing the pulse frequency with the heart rhythm during treatment can reduce the incidence of arrhythmias .
Photodynamic therapy (PDT) depends on three components: photosensitive compounds, visible light, and oxygen. Photosensitive compounds selectively accumulate in hyperproliferative target cells, which then undergo necrosis and apoptosis under the action of visible light and reactive oxygen species . In vitro experiments, confirmed that the mechanism of photodynamic therapy, which is to change the permeability of mitochondrial membrane and eventually lead to the death of target cells, suggesting that the regulation of mitochondrial membrane permeability-related proteins may be the key to the efficacy of photodynamic therapy . This study focuses on vascular targeted photodynamic therapy (VT-P). Flegar et al.  made a comparison between VTP and RP, and the conclusion was not optimistic. However, the follow-up in this study was weak, and there was no matching between VTP and RP patients, at the same time only 79% of patients received MP-MRI and targeted needle biopsy before VTP, resulting in biased results. Compared with active monitoring, VTP still had a greater advantage. After 4 years, the negative rate of biopsy in the VTP group and the active monitoring group was 50% (104/206) and 14 (30/207), respectively. The probability of further treatment after VTP was also lower. There are some side effects of VTP, and Flegar et al.  found that 12% of the patients had obstruction of the bladder opening. Grade 3 treatment-related adverse effects occurred in 12% (6/50) of patients included in their study. Besides that, urination and erectile function scores decreased after VTP, and it took longer for patients to return to baseline [52, 53]. VTP is also a promising treatment for localized prostate cancer. However, there are few studies on VTP, and they are small sample studies, with relatively poor oncology outcomes, and more and longer follow-up is needed to determine its efficacy and side effects.
Figure 1 shows the focal therapy strategies in clinical application. Table 1 is a summary on key clinical study of different types of focal treatment for prostate cancer.
Combined with the above discussion, the following types of patients can also be considered for focal treatment: (1) newly detected prostate cancer patients unwilling to accept active monitoring; (2) Wish to maximize the preservation of original function; (3) Old age or can not tolerate general anesthesia surgery. Despite the lack of long-term follow-up data, focal therapy remains a promising treatment option for localized prostate cancer. Nevertheless, a consensus of indications ,as well as a more standard treatment regimen needs to be reached by domestic and international experts before it can be widely used, meanwhile its long-term oncology outcomes and impact on patient quality of life must be thoroughly analyzed.
We thank Dr. Sanjay Gupta (Case Western Reserve University & UH Cleveland Medical Center) for his proofreading for the review.
All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. Approval from institutional ethical committee was taken.
Availability of data and materials
All data generated or analysed during this study are included in this publication.
STC and SZW wrote the manuscript draft and prepared the figures and tables. JL and JLH edited the final manuscript. JNL approved the final manuscript and came up with the topic.
All authors declare no competing interests.
This work was funded by Sichuan Provincial People’s Hospital Project (grant number 2022QN01).
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