Focal therapy for prostate cancer has evolved over 2 decades, with advances in imaging, patient selection, treatment modalities, and clinical trials.
Prostate cancer is one of the most common cancers in men, and the diagnosis and management of this disease have evolved considerably over the past 2 decades. In medicine, we are increasingly shifting to active monitoring using advanced diagnostic tools rather than immediate treatment, as appropriate. For men with prostate cancer, when is it time to employ prostate-sparing strategies such as focal therapy (FT), an alternative management strategy for localized prostate cancer compared with standard monitoring or whole-gland treatment options? Also, how has FT evolved as a field overall?
Minimally invasive FT options for patients with prostate cancer have recently evolved from a propositional concept to an increasingly integral option in the armamentarium for this disease, growing from 2 FT modalities to a multitude at present, with additional modalities in clinical trials. Since the early 2000s, the field of FT has grown from small, single-arm feasibility experiments to sophisticated multicenter phase 2 and 3 randomized controlled trials built on standardized imaging, consensus-driven patient selection criteria, and increasingly refined definitions of treatment success.
FT treatment options require only a single session and do not use radiation, targeting only the cancer itself, leaving the rest of the prostate intact. By sparing healthy tissue, it significantly reduces common adverse effects such as urinary incontinence and erectile dysfunction compared with whole-gland treatments.
The most common options include high-intensity focused ultrasound (HIFU) and cryotherapy. HIFU uses precise, concentrated ultrasound energy to destroy cancer cells, whereas cryotherapy uses extreme cold to freeze cancerous tissue. An additional commonly used modality is irreversible electroporation (IRE), which uses short electrical pulses to treat cancer cells. A benefit of any form of FT is that all other treatment options remain open to patients if needed, with ongoing monitoring.
I’ve dedicated my career to improving prostate cancer diagnosis, establishing a focal therapy program for properly selected patients, especially as imaging modalities improve accurate detection and localization of prostate cancer. At Montefiore Einstein Comprehensive Cancer Center, we were the first center in the Bronx to offer HIFU.
The earliest publication on FT for prostate cancer, published in 2002, emerged as a small case series of 9 patients who underwent unilateral cryoablation,1 with lead author Gary Onik, MD, medical director of the Center for Recurrent and High-Risk Prostate Cancer and adjunct professor in the Department of Mechanical Engineering at Carnegie Mellon University, publishing an argument in support of FT shortly thereafter, in 2004.2 Onik argued that management of prostate cancer bears parallels to that of breast cancer, with outcomes having a significant impact on quality of life, and gave support to the concept of targeted, less invasive treatment.
Throughout the first portion of 2000 to 2010, studies evaluating FT were largely IDEAL stage 1 and stage 2a studies: small, exploratory investigations designed to test feasibility and safety. Several studies during this time reported outcomes in small cohorts of 20 to 50 patients undergoing focal HIFU or cryotherapy, relying on extensive template mapping biopsies for patient selection and focusing predominantly on low-risk disease.3-5 Primary end points focused on functional outcomes, including high rates of potency preservation (approximately 90%) and minimal, if any, impact on continence. As secondary end points, oncologic outcomes were reported as biochemical recurrence (BCR) using American Society for Radiation Oncology or Phoenix criteria, which are surrogates for recurrence after whole-gland therapy.
In the latter part of 2000 to 2010, feasibility trials still focused primarily on reporting functional outcomes, but oncologic end points evolved to report biopsy-based outcomes in treated tissue, incorporating MRI into the posttreatment protocol. In addition, patient selection shifted to include men with intermediate-risk disease, as active surveillance for low-risk disease became increasingly utilized. Two small prospective focal HIFU studies reported 6- to 12-month posttreatment biopsy rates, revealing the absence of clinically significant prostate cancer in the treated area in 77% to 89% of men treated.6,7 The 12-month trifecta—pad-free, leak-free, and with erections sufficient for penetration—was achieved in 89% of men treated, supporting ongoing favorable functional outcomes.
In the latter part of this decade, cancer localization evolved from extensive template biopsy mapping to the increasing use of MRI, most commonly post diagnosis. The concept of the “index lesion”—the biologic potential of prostate cancer is driven by a single dominant tumor focus that can often be identified on MRI—was articulated by Hashim Ahmed, MD, PhD, in 2009.8 This provided a framework to shift thinking toward more targeted patient selection and refined clinical trial development with the incorporation of MRI. Between 2010 and 2015, clinical trials began integrating MRI not merely as a supplement but as a core component of trial methodology.
In 2013, a 23-member expert panel published Delphi consensus standards in European Urology, proposing unified criteria for MRI reporting and for separating targeted from systematic biopsy results in trial design.9 This represented a pivotal methodological advance: Without consistent imaging standards, cross-trial comparisons were unreliable.
In 2014, the first international Delphi consensus specifically focused on FT trial design was published.10 Forty-eight experts participated in a 4-stage process that defined optimal trial candidates, specified that biopsies should occur at 6 to 12 months post treatment, and established the focal ablation of clinically significant disease with a negative biopsy at 12 months as a primary trial objective. The consensus also endorsed the routine use of multiparametric MRI (mpMRI), an advanced imaging scan used primarily to detect and assess prostate cancer, for patient selection and posttreatment evaluation wherever possible.
Between 2015 and 2020, the field of FT expanded in terms of both clinical trial development and the breadth of energy modalities. A tremendous expansion of IDEAL stage 2a and 2b studies occurred, along with several stage 3 studies and a long-term stage 4 study. Although early feasibility trials comprised predominantly of cryotherapy and HIFU, this period saw the expansion of energy modalities for FT across the literature with the incorporation of IRE and photodynamic therapy (PDT).11
The more mature studies of this period included stage 3 investigations comparing focal approaches against active surveillance or radical therapy. Notably, a randomized trial comparing PDT to active surveillance enrolled 413 patients, whereas a separate trial comparing vascular-targeted photodynamic therapy vs active surveillance enrolled 263 patients. A propensity score–matched comparison of IRE vs robot-assisted radical prostatectomy (RARP) included 100 patients, and the PART feasibility trial, a prospective feasibility registrational clinical trial (RCT) comparing RARP with partial ablation, enrolled 82 patients by 2017. Together, these studies demonstrated for the first time that randomization between FT and radical therapy was logistically feasible, though not without challenges. Shortly thereafter, CHRONOS-A was an RCT comparing FT (HIFU or cryotherapy) to whole-gland therapy (RT or robotic-assisted laparoscopic prostatectomy). Thirty-six patients were enrolled, although 4 patients (22%) in the radical therapy arm withdrew, demonstrating the ongoing challenge of conducting a balanced RCT comparing focal and whole-gland therapy. At the same time, long-term HIFU outcomes data from a 1032-patient cohort showed 5-year metastasis-free survival, overall survival, and cancer-specific survival rates all at 98%, with 98% pad-free continence.
A concurrent second international Delphi consensus in 2017 refined patient selection criteria: ideal candidates had a prostate-specific antigen (PSA) under 10 ng/mL, intermediate-risk disease (Grade Group 2), cancer foci under 1.5 mL (or under 3 mL if confined to 1 hemigland), and cancer occupying no more than 20% to 25% of the prostate.12 Routine mpMRI adoption was now considered essential for both selection and treatment delivery.
However, this era also exposed ongoing challenges. Most notably, the field lacked a universally accepted definition of “cancer control” after treatment. Studies utilizing BCR after primary FT (Phoenix criteria) showed rates of 0% to 67.5% across studies, reflecting inconsistent definitions and inability to apply whole-gland oncologic outcomes to FT, further underscoring the need for end point standardization.
The current clinical trial landscape is increasingly diverse and complex, with a growing range of energy modalities and the emergence of more robust RCTs comparing FT with whole-gland therapy, as well as multimodal therapeutic approaches.
Ongoing studies include phase 2 trials of focal cryotherapy, transurethral ultrasound ablation, laser thermal ablation, and transurethral water vapor therapy. Multiple RCTs comparing FT with whole-gland therapy are underway, including EMERHIT (NCT05710861; HIFU vs radical prostatectomy with cost analysis), WATER IV PCa (NCT06651632; Aquablation vs RALP for Grade Group 1-3), and CAPTAIN (NCT05027477; transurethral ultrasound ablation vs RP for Grade Group 2/3). Other trials are also beginning to explore multimodal approaches that combine focal ablation with neoadjuvant androgen deprivation therapy (ADT).
In 2024, the FALCON consensus, which included 148 participants across 3 Delphi rounds, addressed remaining areas of uncertainty, though 12 items failed to reach 70% agreement, including the definition of PSA or treatment failure, optimal follow-up protocols, and the appropriate volume of tissue to ablate.13 These persistent gaps highlight that, even after 2 decades, some foundational questions remain contested. The third iteration of the FALCON consensus is underway.
Recent aggregate outcome data continue to demonstrate encouraging medium-term outcomes for FT. A 2025 meta-analysis in European Urology Oncology encompassing 5351 patients found in-field clinically significant prostate cancer recurrence rates of 9% and out-of-field recurrence of 8%, with 5-year freedom from whole-gland therapy or ADT at 81%.14 Functional outcomes were very favorable, including incontinence rates of just 3% and an 11% increase in erectile dysfunction from baseline. A 2024 pooled analysis in Prostate Cancer and Prostatic Diseases, covering 49 cohorts, similarly reported an overall survival rate of 98%, a cancer-specific survival rate of 99.3%, and that 97.1% of patients had low impact on continence.15
FT for prostate cancer has evolved from a pilot concept to a field supported by a maturing evidence base, consensus-driven protocols, and an expanding portfolio of randomized trials. That evolution has not been without challenges, including inconsistent end points, heterogeneity in patient selection, and difficulty balancing equipoise when recruiting men for trials that randomize between focal and radical therapy.
As clinical trials continue to refine and hone definitions of oncologic success with longer-term outcomes and data from phase 3 RCTs, and as trials incorporate multimodal therapy, the concept of FT continues to evolve as both a stand-alone therapeutic option and a potential integral component of multifaceted therapy for prostate cancer. Ultimately, the goal of such dedicated efforts and trials is to impact national guidelines to support FT as a standard-of-care option for certain individuals with prostate cancer.
