Introduction Focal therapy (FT) has been proposed as an alternative approach for treating unifocal intermediate-risk prostate cancer (PCa). Using various available energy modalities, FT aims to achieve the oncological outcomes of radical treatment while minimizing the known side effects of whole-gland therapy. Although a treatment option with robust long-term oncological outcomes has been established, the follow-up strategy after FT remains uncertain. A reliable tool to detect tumor recurrence is essential in oncological treatment. Multiple studies have proposed follow-up protocols for these patients. The most recent publications were summarized by Ong et al.1Common recommendations across these studies include follow-up for at least 5 years post-FT. Half of the included studies did not provide specific recommendations on prostate-specific antigen (PSA) monitoring, whereas all studies endorsed magnetic resonance imaging (MRI) as the preferred imaging modality for surveillance. In addition, systematic and targeted biopsies were recommended, although their timing varied. It is acknowledged that the FT currently lacks long-term follow-up data, and as highlighted in various consensus articles, follow-up protocols remain heterogeneous. Such variability can lead to differences in outcomes and recurrence rates, potentially resulting in nonstandardized studies on FT and raising concerns regarding follow-up strategies. Therefore, an identified need exists to standardize definitions, review the limitations of current tools, and target research. 2. Urgency to standardize definitions One challenge in establishing FT follow-up is the lack of universal definitions for oncological success and PCa recurrence. Several studies define ablation success as negative biopsies in the treated area, whereas others define failure as the need for additional treatment, or, similar to post-radical treatment, by applying the biochemical failure classification based on PSA nadir of +2 ng/mL at 18 months. Sanchez-Salas and Desai2divided success into 2 categories: treated and untreated zones. They suggest that oncological success in the treated areas could be defined as small volume Gleason 3 + 3 or very small volume (<0.2 mL or <7.0 mm diameter) Gleason 3 + 4 disease. In untreated areas, low-risk diseases should be monitored using active surveillance protocols. The authors highlight that treatment success is ultimately defined from the patient's perspective as the eradication of aggressive or clinically significant disease. This raises the question of whether transitioning a patient from radical treatment to active surveillance can be considered successful in a holistic sense. These findings highlight the urgent need to standardize definitions to facilitate comparable results in future analyses. 3. Pitfalls of current surveillance tools PSA levels have traditionally been used as a standard measure to detect PCa recurrence post-radical prostatectomy. However, a retrospective review of high-intensity focused ultrasound (HIFU) in these patients demonstrated that PSA was highly variable in accuracy post FT.3In this study, treatment failure was broadly defined as any secondary treatment, Gleason 3 + 4 or higher disease on surveillance biopsy, metastases, or PCa-related mortality. Among patients with treatment failure, the median PSA was 7.80 ng/mL compared with 6.77 ng/mL in those without treatment failure. PSA variability may result from differences in the amount of tumor and prostate tissue treated, overall prostate volume, local tissue inflammation, and benign prostatic tissue growth after FT. Furthermore, variability may arise from differences in the proportion of PSA secreted by the tumors. Multiparametric MRI (mpMRI) is considered an optimal tool for PCa detection, as its various sequences offer valuable anatomical and functional information, enhancing tumor localization and the detection of possible recurrence. However, its efficacy post-FT remains unclear. Because FT involves the use of energy to ablate cancerous tissue, posttreatment mpMRI images may be affected by inflammatory changes, such as periprostatic fat stranding, parenchymal hemorrhage, extraprostatic necrosis, and imaging artifacts. These changes complicate image interpretations.4 In the early phases post-FT, the ablation zone typically demonstrates an enhancing rim and develops hypointense T2-weighted features, among other temporal changes. Koopman et al.4suggested that dynamic contrast-enhanced imaging (DCE) is the most reliable technique for detecting PCa recurrence after FT with various energy sources and should be included into mpMRI surveillance protocols. Despite the potential value of DCE, postprocedural changes and mixed appearances continue to cause interreader interpretation variability, even among experienced radiologists.5A multicenter retrospective review of patients who underwent focal irreversible electroporation demonstrated that mpMRI missed 67% of clinically significant, biopsy-proven posttreatment recurrences.6These results suggest that, given the limitations of mpMRI, template prostate biopsies should remain the standard of care post-FT. Similarly, a retrospective review of patients post-HIFU demonstrated that MRI recurrence scores (defined as the likelihood of recurrence based on diffusion-weighted imaging or DCE characteristics) showed a sensitivity of 0.42 and a specificity of 0.80 in predicting PCa recurrence.5However, Ahn et al.5suggested that the low prevalence of recurrent clinically significant PCa may contribute to the low sensitivity of mpMRI detection. Notably, the study compared the characteristics of in- and out-of-field recurrences. It was assumed that, in partial ablation, out-of-field recurrences would be easier to predict, as these areas experience fewer post-FT tissue changes. However, the results demonstrated no significant difference in mpMRI performance between predicting in-field versus out-of-field recurrences. Given the unestablished long-term outcomes of FT, the need for close follow-up remains a significant issue. Repeated mpMRI scans and biopsies required for surveillance may negatively impact patients' quality of life. This contrasts sharply with the monitoring regimen post-radical treatment, which involves fewer intensive investigations and more standardized schedules. Further research evaluating patient burden and quality of life in this context is warranted. 4. Promise of emerging research Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is an imaging technique with supportive data in the pretreatment evaluation of initial PCa and in cases of biochemical recurrence.7It therefore holds promise in the context role in FT. A single-arm, prospective, single-center study analyzed the clinical impact of 68Ga-PSMA-11 PET/CT across multiple clinical settings.7A subgroup of 13 patients underwent PSMA PET/CT for restaging after FT, achieving a 100% detection rate of PCa recurrence. Of these, 9 patients experienced a change in stage, and 8 patients experienced a change in management. However, a limitation of this study was the absence of histological validation of PSMA-positive lesions, and it was unclear whether the FT performed was whole-gland or partial ablation. An interim analysis was performed on 10 patients who underwent focal HIFU, and all whom received pelvic PET/MRI using a dedicated hybrid scanner.8In 60% of patients, 68Ga-PSMA-11 PET/MRI detected recurrent disease that was not visualized on standard MRI alone. In true-positive lesions, the maximum standardized uptake value was significantly correlated with the total tumor burden. However, this analysis was conducted on a selected subgroup of patients with a positive biopsy and negative mpMRI; therefore, the true sensitivity and specificity of PSMA cannot be generalized. Nonetheless, these studies provide promising results that warrant investigation in larger prospective studies. Systematic transrectal ultrasound (TRUS)–guided biopsy is an established method for enhancing biopsy techniques. However, conventional TRUS lacks specificity for diagnosing PCa, particularly in the absence of clear hypoechoic lesions. However, technical improvements in TRUS have emerged to address these limitations. One such technique is contrast-enhanced TRUS (CEUS), which exploits the nonlinear behavior of contrast bubbles to assess perfusion and vascular architecture, thereby differentiating cancerous tumors from benign tissue.9Compared with mpMRI, CEUS is potentially a more cost-effective and widely available alternative. One study examined the use of CEUS in combination with T2-weighted MRI at follow-up intervals of up to 12 months after whole-gland or hemiablation with HIFU.9CEUS demonstrated an absence of microvascularization or perfusion in ablated zones with atrophy. Although the results were not compared with post-FT biopsy histopathological findings, they suggest that CEUS can be utilized to monitor the reduction in necrosis and tumor volume. Molecular biomarkers have generated considerable interest and represent an emerging area of research. Because of the challenges of monitoring patients post-FT, biomarkers may provide further information to established prognostic tools such as PSA and MRI. Currently, DNA methylation biomarkers are under investigation. A recent study performed DNA methylation analysis of selected tumor suppressor genes.10The results demonstrated that DNA methylation biomarkers, obtained from DNA extracted from urine sediment, in combination with PSA or PSA density improved the detection of clinically significant PCa, thus potentially offering a noninvasive method of monitoring post-FT. 5. Conclusions Our review highlights that FT currently lacks global consensus on follow-up protocols. Definitions of treatment success vary widely, and although PSA, mpMRI, and biopsies are considered standard surveillance tools, each has important limitations. Further large prospective studies are needed to better evaluate follow-up strategies and to explore the potential of alternative modalities, such as PSMA PET, advanced TRUS techniques, and molecular biomarkers.
Lim et al. (Thu,) studied this question.