Focal therapy (FT) for prostate cancer is a minimally invasive approach that targets and destroys only the area of the prostate containing cancer, while leaving the surrounding healthy tissue intact. This stands in contrast to whole-gland treatments like radical prostatectomy or full-prostate radiation, which treat the entire prostate regardless of where the cancer is located.
Several energy sources can be used to ablate (destroy) the targeted cancer tissue: high-intensity focused ultrasound (HIFU), cryotherapy (extreme cold), irreversible electroporation (IRE), laser ablation, photodynamic therapy, and focal brachytherapy (implanted radiation seeds). Each has different properties in terms of tissue penetration, side effect profiles, and technical requirements.
The goal of focal therapy is to achieve cancer control comparable to radical treatment while avoiding the significant side effects associated with whole-gland therapy, including urinary incontinence and erectile dysfunction. Ideally, men treated with FT would have their management 'de-escalated' closer to active surveillance, with much lower rates of functional impairment.
Despite its conceptual appeal, the evidence supporting FT remains limited. There is a shortage of long-term data and randomized controlled trials, and the criteria used to select patients, the clinical endpoints measured, and the definitions of treatment success vary widely between published studies -- making comparisons difficult.
Multiple international oncology organizations have published guidelines on prostate cancer management, and several expert groups have published consensus statements specifically addressing focal therapy. However, these documents vary considerably in their recommendations, reflecting the underlying uncertainty in the field.
This review article systematically examined the major international guidelines -- specifically the European Association of Urology joint guidelines (EAU+) and the American Urological Association joint guidelines (AUA+) -- as well as the National Comprehensive Cancer Network (NCCN) guidelines, alongside published consensus statements from 2015 onward.
The primary question the authors sought to answer was whether current evidence supports a unified global guideline for focal therapy in prostate cancer, covering patient selection, technique, and follow-up -- or whether the field remains too immature for that consensus.
The search strategy used PubMed and Ovid Medline databases to identify consensus statements published in English since 2015. Reference lists were manually checked and ongoing clinical trials from ClinicalTrials.gov and the Australian New Zealand Clinical Trials Registry were also catalogued.
The EAU+ guidelines conducted a systematic review of focal therapy studies published between 2000 and 2020. Of 1,119 articles identified, only four met inclusion criteria, and only one was prospective. Endpoints were heterogeneous and risk of bias was moderate to high. Based on this evidence base, the EAU+ recommendation is that FT should only be offered within a clinical trial or well-designed prospective cohort study for newly diagnosed low- and intermediate-risk disease.
The EAU+ position statement echoed these cautions with five key conclusions, including that imaging cannot yet reliably identify all high-risk cancer clones within the prostate, the oncological effectiveness of FT remains unproven without comparative data, and patients should only be treated within a clinical trial with predefined outcome criteria.
The AUA+ guidelines classified their FT recommendations as expert opinion (low-grade evidence) and also recommend that FT be performed only in a trial context. Patients should be informed of the lack of robust evidence and warned they may require further treatment. For HIFU specifically, the guidelines note that apical tumor location increases the risk of cancer persistence after treatment.
The NCCN guidelines state that cryotherapy and other local therapies are not recommended as routine primary therapy for localized prostate cancer due to lack of long-term comparative data. For patients with recurrence after radiation therapy, only cryosurgery and HIFU are mentioned as local salvage options in the absence of metastatic disease.
A critical first step in advancing focal therapy research is establishing consistent definitions. Without standardized terminology, results from different studies cannot be meaningfully compared. Two major Delphi consensus projects -- by Postema et al. (2016) and Lebastchi et al. (2020) -- have attempted to standardize key definitions, with consensus defined as agreement exceeding 80%.
Key agreed definitions include: focal therapy as an anatomy-based strategy targeting specific prostatic zones; the index lesion as the dominant tumor defined primarily by grade; ablation failure as confirmed failure of the technique to destroy tissue in the treated zone; and selection failure as inappropriate patient selection, evidenced by the short-term appearance of metastatic or locally advanced disease.
However, agreement was not reached on several important points. Whether significant cancer found in short-term biopsies inside or outside the treatment zone constitutes selection failure remains unresolved. Additionally, Lebastchi et al. could not achieve consensus on whether an index lesion can be defined solely by being the largest lesion, or whether Grade Group 1 cancers qualify as index lesions.
These definitional gaps are not trivial -- they directly affect how clinical trial endpoints are designed, how treatment success is measured, and how patients are counseled. Until these ambiguities are resolved, comparing results across institutions and trials remains inherently difficult.
Six consensus statements on patient selection for focal therapy were identified, using Delphi methods or expert panels. All six agreed that multiparametric MRI (mpMRI) is the imaging modality of choice for diagnosing prostate cancer before focal therapy and that both targeted and systematic biopsies are required prior to treatment.
Agreement on disease characteristics was more variable. All studies agreed that FT should generally be reserved for men with Gleason score 6 or 7 cancer, though there was disagreement about how much Gleason 6 cancer is acceptable to leave untreated. Studies used different risk classification systems (D'Amico versus NCCN), making direct comparison difficult.
Patient factors such as age and life expectancy did not consistently reach consensus across studies. Some panels agreed that age should not be a determinant; others could not reach consensus on age thresholds. WHO performance status and life expectancy of greater than 10 years were agreed upon by some but not all expert groups.
A dedicated Delphi consensus on molecular biomarkers in focal therapy concluded that current evidence is insufficient to include molecular tests in routine clinical decision-making for FT selection, and that mpMRI is currently more useful and accessible than molecular biomarkers. PSA and PSA density were identified as having potential future roles, but most commercial molecular tests had unclear or no consensus role.
Four consensus statements on post-treatment follow-up were identified. Three agreed on broadly similar protocols: PSA testing every 3 months for the first year, then every 6 months; mpMRI at around 6 months; and a systematic plus image-guided biopsy at 6-12 months after treatment. Functional outcomes (urinary, sexual) should be assessed every 3-6 months until stable.
A key area of agreement is that mpMRI should be a standard part of follow-up after focal therapy. However, mpMRI combined with targeted biopsy alone is insufficient for post-treatment surveillance -- standard random biopsies remain necessary alongside targeted ones. MRI-guided biopsy should be performed when an mpMRI lesion is identified.
A concerning gap in follow-up protocols is the complete absence of PSMA PET/CT in any current consensus recommendation. Given that PSMA PET/CT can identify tumors not visible on MRI and is rapidly being incorporated into primary prostate cancer staging, its exclusion from FT surveillance protocols may need to be revisited as evidence accumulates.
The accuracy of mpMRI in detecting residual cancer after focal therapy has been questioned by recent data showing low diagnostic accuracy for residual disease after IRE treatment. This reinforces the need for routine re-biopsy rather than relying on imaging alone -- a point of strong agreement across all follow-up consensus statements.
Well-designed randomized trials comparing FT to standard of care are needed but face significant practical obstacles. Powering a non-inferiority trial on metastasis-free survival for low- and intermediate-risk prostate cancer would require over 1,000 patients and 12-15 years of follow-up -- a scope that has led to the premature closure of several prior prostate cancer trials.
For low-risk disease, the expanding use of active surveillance means that the relevant comparison for FT is increasingly active surveillance itself rather than radical treatment. Whether FT provides meaningful benefit over surveillance in low-risk patients -- with acceptable costs and side effects -- remains an open question. Some patients with high-volume Gleason 6 or PI-RADS 4-5 lesions may represent a 'sweet spot' worth exploring.
Intermediate-risk prostate cancer is considered the most appropriate target for focal therapy. A matched-paired cohort study showed comparable oncological outcomes between FT and radical prostatectomy over an 8-year period, and in-field clearance rates following FT are high. This cohort allows a genuine de-escalation from radical treatment while maintaining acceptable cancer control.
Salvage treatment after FT failure is feasible, with salvage radical prostatectomy showing comparable oncological and functional outcomes to primary surgery in some series. However, higher positive margin rates have been reported at non-specialized centers, suggesting that salvage surgery should be concentrated at high-volume institutions experienced in post-FT cases.
Advances in imaging technology may significantly change how patients are selected for focal therapy. PSMA PET/CT can identify lesions not visible on mpMRI, and when concordance is achieved between MRI, PSMA PET/CT, and biopsy histology, clinicians can have greater confidence that no undetected significant cancer exists outside the planned treatment zone.
The maximum standardized uptake value (SUVmax) on PSMA PET/CT may also serve as a prognostic marker, helping identify patients at higher risk of recurrence who may not be ideal candidates for active surveillance or focal therapy. This could improve patient selection and reduce the risk of undertreating high-risk disease masked by imaging limitations.
In summary, this review confirms that no globally accepted guideline yet exists for focal therapy planning, technique, or follow-up. Consensus statements across the past decade are heterogeneous, making it difficult to design studies that will change clinical practice. There is broad agreement that FT should be performed within clinical trials wherever possible.
For centers without access to formal trials, clinicians are encouraged to collaborate and publish results prospectively, contributing to the growing evidence base. As data from ongoing comparative trials mature, it is expected that evidence-based guidelines will gradually replace expert opinion as the foundation for focal therapy recommendations.