Abstract
Management of recurrent prostate cancer following radiotherapy and subsequent radical prostatectomy poses considerable challenges due to potential complications for patients. Focal therapies have emerged as a burgeoning approach in prostate cancer treatment. Research indicates that ablative therapies exhibit encouraging oncological efficacy while maintaining acceptable functional outcomes in salvage interventions. Here, we present a contemporary review of focal therapy treatment modalities as well as oncologic and functional outcomes.
Introduction
Radiation therapy is a standard of care treatment option in men with localized, clinically significant prostate cancer, and can provide excellent oncologic outcomes. However, 10%–15% of patients will recur after treatment, and some of these patients will have isolated local recurrence. 1 If left untreated, a patient with overall good health and longer life expectancy may experience symptoms from locally advanced disease, distant metastasis, and sometimes death from prostate cancer. Localized treatment of radio-recurrent prostate cancer through salvage therapy may improve oncological outcomes while also preventing symptoms that can develop with locally advanced or metastatic disease.
Radical prostatectomy, an established salvage option, is associated with poor functional outcomes and high risk of complications. Many surgeons are reluctant to offer this treatment due to the morbidity rates. Likewise, some of these patients are treated with androgen deprivation therapy (ADT), which is associated with numerous side effects.
Focal ablation can be a good treatment option for radio-recurrent prostate cancer in well selected patients. Ablative therapies, particularly cryotherapy, have been used for treatment of locally recurrent disease. Here, we present a brief review and update of ablative therapy treatment options and their oncologic and functional outcomes in patients with radio-recurrent prostate cancer. We reviewed the existing literature of ablative energy sources commonly used in the United States and we included key studies published over the last 15 years between 2009 and 2024.
Cryoablation
Oncological Outcomes After Salvage Cryotherapy.
PSA: Prostate specific antigen, BCR: Biochemical recurrence, PFS: Progression-free survival, OS: Overall survival, DSS: Disease-specific survival, CSS: Cancer-specific survival, MFS: Metastasis-free survival, RP: radical prostatectomy.
Functional Outcomes and Complications After Salvage Cryotherapy.
ED: Erectile dysfunction, IIEF: International Index of Erectile Function, RP: radical prostatectomy.
Several have focused on salvage cryotherapy, specifically, whole gland ablation.3-7 The median PSA values before salvage treatment ranged from 3.8 to 7.6 ng/mL, and the average follow-up times ranged from 18 to 124 months (Table 1). The majority of patients had Gleason grade group (GG) 1 before undergoing salvage cryotherapy, and all studies used the Phoenix criteria to define biochemical recurrence (BCR). 8 The studies provided rates of BCR for different follow-up periods, ranging from 1 to 8 years. The BCR rate ranged from 15% to 59.8%, depending on follow-up time. Some studies have reported survival outcomes, including metastasis-free survival (MFS), cancer-specific survival (CSS), desease specific survival (DSS), and overall survival (OS). MFS, CSS/DSS, and OS ranging from 52% to 90%, 70% to 98.8%, and 54% to 90%, respectively, with varying follow-up times (Table 1). Exterkate et al. defined BCR using PSA>0.5 ng/mL in addition to the Phoenix criteria. Based on PSA level>0.5 ng/mL, BCR occurred in 67% of patients at a median follow-up of 36 months and in 76% of patients at 8 years. According to PSA nadir, 22% of patients with PSA≤0.1 ng/mL developed BCR, while 67% of patients with PSA>0.1 ng/mL developed BCR. 6
While most studies combined whole-gland and focal treatment in their report, Wimper et al. published their experience with focal therapy alone. This was a 10-year single-center experience of MRI-guided salvage focal cryoablation. 9 In the cohort,15 patients underwent radical prostatectomy in the past, while 99 patients were treated with radiation alone. Recurrence was defined based on any of radiologic, histopathologic, or biochemical criteria. Patients underwent biopsy after treatment. According to the authors, recurrence-free survival defined through repeat prostate biopsy was considered more important than PSA in evaluating patients after focal salvage cryotherapy, as PSA levels can be affected by normal prostate tissue and therefore cannot be evaluated by the Phoenix criteria alone. The 1-year recurrence-free survival rate was found to be 77.5%, while the 5-year rate was 28%.
Rectourethral fistula is the most serious complication of cryotherapy and studies showed that ranging from 0.9% to 5.3%. The studies presented other significant complications including urethral sloughing, which was reported between 12% to 14.2%, and lower urinary tract obstruction, which was reported between 0.9% to 10.4%. Urinary retention rates varied from 3.6% to 25.7% for whole gland ablation and from 5.6% to 15.8% for focal ablation. Tan et al. showed that the urinary retention was significantly higher in whole gland ablation compared to focal ablation [22.4% vs 5.6 (P < 0.001)]. 3 Table 2 summarizes the studies in terms of functional outcomes and complications.
The prevalence of urinary incontinence for whole gland ablation varies depending on the definition in the studies. If defined as any degree of urine leakage, rates range from 9% to 54.9% of whole gland ablation. If defined as more than 1 pad per 24 hours, rates range from 16.4% to 19%.5,6 The urinary incontinence rate for focal ablation ranges from 6.1% to 9.3%.3,9
Assessing erectile dysfunction (ED) was challenging due to the low International Index of Erectile Function (IIEF) scores among patients at baseline. Tan et al. reported an ED rate of 59.6% for whole gland ablation. 3 Another study by Exterkate et al reported 92% ED. 6
In summary, contemporary studies have shown that in the modern era, salvage cryotherapy is a safe treatment option in patients with radio-recurrent prostate cancer and can provide reasonable oncologic control. Risk of serious adverse events of Clavien III or higher is low. The most common long-term complications include urinary incontinence, retention, urethral sloughing and erectile dysfunction. Understanding these outcomes is essential when counseling patients about their treatment options.
High-Intensity Focused Ultrasound (HIFU)
High Intensity Focused Ultrasound (HIFU) treatment is a method of tissue ablation that uses ultrasound waves. The method generates temperatures ranging from 60°C to 90°C in the tissue, causing thermal damage that results in coagulation necrosis, protein denaturation, and cellular cavitation. During the procedure, rectal cooling is actively performed to prevent rectal injury caused by high temperatures, which is considered the most serious complication. 10 The main limitation of HIFU is the penetration (up to 4 cm), which restricts access to lesions in large glands (above 40cc), as well as anterior and apical lesions. 2
Oncological Outcomes After Salvage HIFU
PSA: Prostate specific antigen, BCR: Biochemical recurrence, PFS: Progression-free survival, OS: Overall survival, CSS: Cancer-specific survival, CEFS: Composite endpoint free survival (BCR and/or positive localized or distant imaging and/or positive biopsy and/or systemic therapy and/or metastases and/or prostate cancer specific death), *Progression was defined by the Phoenix criteria, a positive biopsy or introduction of additional salvage therapy such as ADT.
Functional Outcomes and Complications After Salvage HIFU
ED: Erectile dysfunction, CTCAE: Common Terminology Criteria for Adverse Events, IIEF: International Index of Erectile Function, *Urinary incontinence was graded according to the Ingelman-Sundberg score (strong, moderate, minimal effort: grade 1, grade 2 and grade 3, respectively).
A prospective clinical trial was conducted at 16 sites in North America, 78 out of 100 men underwent biopsy after whole-gland salvage HIFU at 12 months; 70 men achieved a PSA nadir of 0.5 ng/mL or less, and 50 men achieved the combined primary endpoint of a PSA nadir and a negative biopsy at 1 year. 13 In a study by Kanthabalan et al., 150 patients who underwent focal salvage HIFU after radiation treatment had their data retrospectively reviewed. 14 Composite failure, which was the primary outcome, was found in 60% of the patients at 3 years. The OS was 92% at 5 years, the BCR was defined using the Phoenix criteria, and 52% of the patients met the criteria at 3 years (Table 3).
The symptoms and complications following salvage HIFU were distributed heterogeneously. The frequency of urinary incontinence and urethral stricture ranged from 7% to 47% and 8% to 20%, respectively (Table 4). The frequency of rectourethral fistula ranged from 2 to 5% and osteitis pubis has been reported in some studies.13,14
When comparing cryoablation and HIFU for salvage therapy after radiation, it is important to consider their respective benefits and drawbacks. A recent meta-analysis evaluated all nonsurgical salvage options for locally recurrent prostate cancer after primary definitive radiation therapy, including cryotherapy, HIFU, salvage radical prostatectomy, and re-irradiation. 15 This comprised of 27 studies looking at cryotherapy, 16 at HIFU, and one study including both modalities were selected for this meta-analysis. The median PSA ranged from 1.93 to 9.5 ng/mL, and the median GG reported was mostly 2. The pooled rate of biochemical recurrence-free survival at 5 years for cryotherapy was 0.52 (95% CI 0.33-0.69).
Cryotherapy had the highest 5-year biochemical control rate among all salvage therapies. The pooled BCR-free survival rate for HIFU at 5 years was 0.29 (95% CI 0.15-0.48) and this was significantly lower than that for the overall patient population. Toxicity was assessed by the rates of genitourinary and/or gastrointestinal toxicity ≥ grade 3 (GU3, GI3) and any grade of common GU adverse events. Subgroup analyses revealed low rates of GU3 in patients treated with cryotherapy (0.09, 95% CI 0.04-0.14; I2 = 91%). Patients who received HIFU had the highest GU3 rate (0.22, 95% CI 0.12-0.31; I2 = 90%) among all salvage therapy modalities. There was no significant difference in the incidence of GI3 between the different salvage therapies.
Irreversible Electroporation (IRE)
Irreversible Electroporation (IRE) is an ablation technique that employs high-voltage, low-energy electricity to create nanopores in the cell membrane, leading to soft tissue damage. IRE is performed with transperineally inserted probes under general anesthesia in the lithotomy position. The ablation area ranges from 5 mm to 20 mm, and the probes are placed at least 5 mm away from sensitive structures such as the urethra, sphincter, and rectum to ensure their protection during the procedure. 10 Although IRE is not as commonly used as cryotherapy and HIFU in patients with recurrence after radiotherapy, studies on this subject have been increasing in recent years. We reviewed a few recent articles that focus on IRE in a salvage setting.
In 2017, a single-center study was conducted with 18 patients. 16 The patients' median age was 71 years, PSA level was 3.5 ng/mL, and prostate volume was 23 mL, with a follow-up period of 21 months. In this cohort, 11 patients had intermediate-risk disease, while 7 had high-risk disease. Three patients developed BCR after IRE treatment according to the Phoenix criteria. 8 Thirteen patients underwent MRI at 6 months postoperatively, with 11 of the 13 patients showing negative results and 2 patients showing positive results with out-of-field recurrence. Ten patients underwent biopsy after salvage IRE, of whom 8 were benign. Five patients experienced grade 1 adverse events, while 2 experienced grade 2 adverse events. No patients experienced severe adverse events or developed rectourethral fistula. EPIC sexual function score at 6 months decreased significantly from baseline. Based on the quality of life assessment, only the EPIC sexual function summary score showed a statistically significant decrease at 6 months compared to baseline. Three patients experienced incontinence and required pads, and 1 patient continued to have incontinence for 12 months. Despite the small sample size, this study demonstrated the feasibility and safety of focal salvage IRE with short-term outcomes.
The FIRE trial looked at 37 patients treated prospectively with salvage IRE. 17 The majority of patient in the cohort had intermediate risk disease (75.5%) and 24.5% had high risk disease. Median PSA was 3.5 ng/mL. All patients underwent mpMRI at 6 months and transperineal template mapping biopsies at 12 months. Four (11%) patients developed local recurrence and 6 (16%) developed metastasis. 73% of patients were disease free at 1 year. In terms of complications and side effects, 7 (19%) patients developed urethral sloughing requiring transurethral resection. Other common but low-grade adverse events included self-limiting urinary urgency, frequency, and hematuria. At 12 months, 93% of patients were continent. 35% of men reported erectile function sufficient for intercourse prior to treatment and this deteriorated to 15% after treatment. IRE offered patients another option for local oncologic control with acceptable side effects.
A study conducted by Geboers et al., in 2023 involved a single-center series of men with radio-recurrent prostate cancer treated with IRE. 18 The study enrolled 74 patients, and all participants had at least 6 months of follow-up after treatment. Patients underwent a follow-up biopsy at 12 months. The median PSA at treatment was 5.4 ng/mL and the median prostate volume was 36 mL. Of the patients, 56 were classified as GG 2 and 3, while 16 were classified as GG 4-5. During the median 48 months, 77% of the patients achieved local control and did not require additional salvage therapy. Disease progression occurred in 22 patients. The overall MFS rate was 91% at 4 years, the 5-year PFS rate was 60%, and the median time to metastases was 8 months. Eight patients developed grade 3b complications after the procedure. Seven patients experienced urethral sludge and required transurethral resection, whereas 1 patient developed a rectal fistula. Continence was preserved in 93% of the patients after salvage IRE. Erectile function was already low at baseline and decreased from 38% to 23% at 12 months after IRE. This study supports the efficacy of focal IRE in achieving oncological control with acceptable morbidity.
Transurethral Ultrasound Ablation (TULSA)
In 2020, Anttinen et al. published the first study on TULSA with salvage indication. 19 Eleven patients were enrolled in this prospective study. The median PSA level before treatment was 7.6 ng/mL, and the median prostate volume was 21g. BCR was defined based on Phoenix criteria. There were 1 grade 3 and three grade 2 adverse events related to the intervention. At 12 months, positive biopsy results were found in 3 out of eleven patients. Among them, 1 patient experienced in-field recurrence with GG2, whereas two patients experienced out-field recurrence with GG4. Additionally, 1 patient with GG4 experienced BCR.
Transperineal Laser Ablation (TPLA)
Five men diagnosed with low-risk radiorecurrent prostate cancer underwent TPLA in a study. 20 After the first month, PSA levels decreased by >70% at 18 months in all patients. There were no significant differences in the IIEF and IPSS scores between the baseline and 18-month follow-up. This study was the first to evaluate TPLA in salvage indications, despite the small sample size.
Conclusion
Treating recurrences after radiotherapy with radical prostatectomy can lead to significant complications for the patient. Focal therapies are increasingly used in the treatment of prostate cancer. Studies have shown that ablative therapies have promising oncologic results with acceptable functional outcomes in salvage treatment. Head-to-head comparison between treatment modalities are lacking however, energy source does not necessarily dictate practice. Many experts believe that other factors such as tumor location (anterior vs posterior, base vs apex), tumor size, prostate size, and presence of calcifications and artifacts will have a stronger influence of the selection of treatment modality.
This review highlights oncologic and functional outcomes of some of energy sources most commonly encountered in the United States in the contemporary era. This data is particularly helpful for patient counseling on oncologic and functional outcomes.
While there has been tremendous advancement in the field of focal ablative therapies over the last two decades, many questions are still left unanswered. Surveillance strategies after treatment is still unclear. More research is needed to improve our understand of PSA kinetics, radiographic imaging interpretation post-treatment and long-term outcomes.
Footnotes
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Alice Yu MD, MPH: Angiodynamics. Scientific advisor. Mustafa Dinckal MD: none. Julio Pow-Sang MD: Angiodynamics. Scientific advisor.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
