Current focal therapies for the treatment of low- and intermediate-risk prostate cancer

Active surveillance (AS) and radical treatment (such as radical prostatectomy [RP] or external radiotherapy [RT]/brachytherapy [BRT]) are the standard therapeutic options for treatment in localized prostate cancer (PCa).1 The oncological efficacy of RP and RT/BRT has been validated by studies with a long follow-up period. Several studies have demonstrated that prostate cancer-specific mortality is low whatever the therapeutic approaches used but with a difference in genitourinary and gastrointestinal toxicity which affects the patient’s quality of life.1,2 Instead, AS is associated with a greater incidence of disease progression and metastasis,2 especially in patients with intermediate-grade carcinoma.3–7 The choice of treatment strategies is based on the risk assessment, to avoid under- and overtreatment and reduce radical treatments’ morbidity. Focal therapies (FTs) would be an ideal approach for localized and small tumors and for low- and intermediate-grade disease. FTs are exclusively used to treat the clinically significant lesion (“index lesion”), sparing the neighboring structures and resulting in less morbidity compared to radical treatments that involve the entire gland. Moreover, the oncological efficacy is preserved according to the theory that index lesion determines the risk of metastasis and patient’s prognosis. Multiparametric magnetic resonance imaging (mpMRI) improves staging and detection of high-grade lesions, and MRI-transrectal ultrasound (TRUS) fusion-guided systems allow targeted biopsy on index lesion. FTs applications are closely linked to patient selection. The International Delphi Consensus Project in 2017 provided details for the selection of patients with clinically localized PCa for FTs: low-/intermediate-risk tumors (including Gleason score 4+3), tumor foci <1.5 ml on mpMRI or <20% of the prostate, or tumor foci up to 3 ml on mpMRI or 25% of the prostate if located on a hemi gland. There was no consensus for patients with high-risk PCa, whose prostate-specific antigen (PSA) >10 ng ml−1, cancer foci >3 ml or 25% or crossing the midline, and for patients with severe lower urinary tract symptoms (LUTS).8 Different types of FTs and their applications are shown below. FOCAL CRYOTHERAPY (FC) FC pursues tissue ablation by inducing temperatures below −40°C. Tissue damage is mediated by the denaturation and dehydration of proteins, the rupture of cell membranes, the reduction of cellular metabolism, and finally, the thrombosis of the microvascular system. Cryoablation should be reserved mainly for anterior locations in the International Society of Urological Pathology (ISUP) grade 2 or 3 PCa that do not border or invade the urethra or sphincter. Several authors reported different clinical outcomes after FC with the following range: biochemical relapse-free survival in 75.0%–90.5% patients, recurrence in-field in 1.40%–7.38% patients, recurrence out-of-field in 7.38%–21.00% patients, urinary incontinence in 0–3.6% patients, and erectile dysfunction in 10%–42% patients.9–14 HIGH INTENSITY FOCAL ULTRASOUND (HIFU) HIFU induces thermal damage to tissues reaching temperatures between 60°C and 90°C, leading to coagulative necrosis, cellular cavitation, and protein denaturation. It is associated with a higher incidence of urethral stricture and acute urinary retention, as well as a lower rate of erectile dysfunction compared to radical radiotherapy, with rectal damage being the most feared complication. Anterior location and a lesion-skin distance greater than 4 cm can limit energy administration and reduce oncological efficacy. After HIFU, we can obtain a biochemical relapse-free survival in treated patients between 78% and 85%, recurrence in-field of 4%–26% patients, recurrence out-of-field of 2%–34% patients, urinary incontinence of 1%–34% patients, and erectile dysfunction of 20%–39% patients.15–20 PHOTODYNAMIC THERAPY (PTD) PTD uses photosensitizing drugs and an infrared light source emitted through intraprostatic catheters which induces the formation of free radicals. This process led to thrombosis and coagulative necrosis, in addition to cytotoxicity and activation of a reactive immune response.21–23 A randomized clinical trial with 48 months of follow-up showed recurrence in-field in 0–25% of treated patients, rate of conversion to radical treatment at 4 years of 24% patients, urinary incontinence in 9.3%–10% of patients, and erectile dysfunction in 23%–38% of patients.21 IRREVERSIBLE ELECTROPORATION (IRE) IRE uses low-energy, high-voltage, electrical pulses to create permanent pores in the cell membrane, which leads to cell death. For this treatment, the biochemical relapse-free survival is described in 83%–95% patients, recurrence in-field in 6%–17% patients, recurrence out-of-field in 4.7%–24.3% patients, urinary incontinence in 0–9.1% patients, and erectile dysfunction in 3%–50% patients.24–28 FOCAL LASER ABLATION (FLA) FLA is performed conducting energy through a laser fiber inserted into the tumor, inducing cell necrosis.29–31 In a cohort of 36 patients undergoing FLA, failure-free survival was observed in 83% of patients at 5 years of follow-up. However, among these patients, 40% developed a recurrence in the field of therapy.29 FOCAL BRACHYTERPY Low-dose brachytherapy (LDR-BT) is a treatment option that involves implanting radioactive iodine-125 seeds permanently into the area of the prostate where the cancer has spread. Several studies with a median number of 30 patients (range: 5–50) and a median follow-up of 24 months, reported biopsies in 90%–100% of patients after treatment, with no reported differences in pre- and post-procedural continence scores but often a significant decrease on erectile function.32–35 CONCLUSIONS The most appropriate focal ablation modality has to be chosen depending on the characteristics of the PCa. For tumors located posteriorly in the gland and close to the vascular nervous bundle, HIFU is considered more appropriate, due to the shorter focal distance and more precise identification of the target. For anterior tumors, the transperineal approach, such as cryotherapy, is preferable. Focal brachytherapy could be considered for apical tumors near the sphincters as it is associated with higher continence rates.36 The data suggest that FTs are feasible, safe, and effective for highly selected patients with localized PCa at low-to-intermediate risk, with acceptable rates of late urinary and sexual toxicity. Short-term oncological efficacy has been demonstrated, supporting their usefulness in low-risk patients (Table 1). However, no randomized clinical trial comparing FT with radical treatment has been published, clinical experience regarding long-term effects remains limited and there is wide heterogeneity in the definition of oncological outcomes.Table 1: Literature evidence about focal therapiesManagement of localized recurrence after FT depends on the risk group, in-field or out-of-field recurrence and the patient preference. The options include: repeat FT, radiotherapy, and prostatectomy.37 Salvage prostatectomy has been reported to have similar oncological and functional outcomes compared to primary radical prostatectomy.38,39 In conclusion, more homogeneous and comparative studies with standard treatments are needed to better define patients for whom FTs are really useful. To date, with available evidence, none of the FTs can be considered a standard option for treatment but an alternative to active surveillance in low-risk PCa. COMPETING INTERESTS The author declares no competing interests.