Focal therapy is an ablative technique that can be utilized as an alternative treatment modality to traditional surgery or radiation. It has the advantage of being minimally- or non-invasive, as well as potentially reducing adverse effects on urinary and sexual function. However, the role of focal therapy in the management of clinically localized prostate cancer continues to remain unclear due to uncertainty about long-term outcomes compared with traditional management modalities. Evidence for outcomes with focal therapy and with high-intensity focused ultrasound (HIFU) was reviewed by Jim C. Hu, MD, MPH, Ronald Lynch Professor of Urologic Oncology and Director of the LeFrak Center for Robotic Surgery at Weill Cornell Medicine-New York Presbyterian Hospital.
For appropriately selected patients, the benefits of focal therapy include preservation of quality of life as well as potential avoidance of death from the disease, Dr. Hu stressed. Emphasizing the hazards of prostate cancer therapy, he cited data from the latest US Preventive Services Task Force (USPSTF) prostate cancer guideline suggesting that of every 1000 patients screened with PSA, 100 will be treated, of whom 3 will avoid metastasis, 1 will avoid prostate cancer-specific mortality and 5 will die from prostate cancer despite surgery.1 Furthermore, on average, 50 will experience erectile dysfunction and 15, urinary incontinence.
The majority of published studies on focal therapy are beset with issues ranging from relatively few patients, methodical flaws in comparisons, heterogeneity in patients being treated or treatments administered, and outcomes reporting, Dr. Hu acknowledged. He noted that a systematic review of focal therapy for the latest European Association of Urology (EAU) prostate cancer guideline update identified only four studies suitable for inclusion (one randomized clinical trial and three retrospective comparisons) for inclusion from a total of almost 1600 located, after exclusion of all those that were noncomparative or single-arm, or enrolled fewer than 50 patients. Even among the 4 studies selected, there was a substantial risk of bias present in three.
The only Level I evidence for vascular-targeted focal photodynamic therapy (PDT) vs active surveillance for low-risk prostate cancer remains the Phase 3 PCM301 trial.3,4 In PCM301, patients randomized to padeliporfin had a lower rate of disease progression (28% vs 58%, HR 0.34, 95%CI 0.24-0.46), a lower rate of requiring radical therapy (6% vs 29%, P<0.01), and a higher rate of negative biopsy (49% vs 14%, RR 3.67, 95%CI 2.5-5.3). Adverse effects on erectile and urinary function with PDT were transient and resolved by 24 months.
Another of the four studies included in the EAU review2 compared HIFU hemiablation of the prostate to robot-assisted laparoscopic prostatectomy (RALP) in the management of predominantly (65%) low risk patients.5 At 36-month follow-up, there was no difference between HIFU and RALP in requirement for salvage therapy (external beam radiotherapy or androgen- deprivation therapy), but 12.5% of patients receiving focal HIFU needed hemiablation due to development of contralateral cancer. Patients receiving HIFU had significantly superior rates of urinary continence at 1 month (82% vs 40%, P<0.01) and erectile function at 24 months (20% vs 44%, P=0.03) compared with those who underwent RALP.
Based on the results of the four studies selected, the EAU review authors concluded that the certainty of the evidence regarding the comparative effectiveness of focal therapy as a primary treatment for localized prostate cancer was low and they questioned whether focal therapy was appropriate in patients with low risk prostate cancer.2 “Many will not benefit but will have transient side effects,” they noted. Based on current data, it may be very difficult for focal therapy to improve overall survival to cancer-specific survival in the active surveillance population due to excellent prognosis with no treatment, echoing the USPSTF data, Dr. Hu reported.
In the absence of high-quality evidence to support the use of focal therapy, an international multidisciplinary consensus panel of experts was convened to create a consensus agreement on post procedural surveillance after focal therapy.6 Using a Delphi method, consensus statements were issued (all >80% consensus) confirming that MRI-visible lesions GGG ≥2 should be used as a target for focal therapy, first PSA measurements every 3 months during the first year after focal therapy and every 6 months thereafter, Dr. Hu explained. The consensus also established multiparametric prostate MRI (mpMRI) as the preferred imaging modality for measuring treatment response, which should be done within 6 months after focal therapy and repeated 12 months after first post- procedural mpMRI. Early contrast enhancement in the treated lesion was agreed to be a sign of focal therapy failure.
Additionally, the panel determined that MRI- targeted biopsy, either in gantry or MRI fusion, should be performed to evaluate the treated lesion as well as a systematic extended sextant biopsy to evaluate the untreated area. The first MRI biopsy should be performed within the first year after focal therapy to assess for in-field persistence, i.e., treatment failure. Systematic extended sextant biopsy should be obtained 6-12 months after focal therapy to assess for out- of-field progression. After a negative initial systematic biopsy, further systematic biopsies are not mandated, but may be obtained at the physician’s discretion or if there are triggering factors such as rise in PSA or imaging abnormalities. Regarding treatment failures, the expert consensus agreement is that in-field failures can be safely offered repeat focal therapy.
The recently reported international Tulsa-PRO Ablation Clinical Trial (TACT) employed transurethral HIFU focused on patients with low and intermediate risk prostate cancer,7 Dr. Hu noted. At 12 months follow-up, in terms of functional outcome recovery, 25% of patients failed to regain erectile function sufficient for penetrative intercourse. Additionally, a small percentage (4%) of men also experienced urinary incontinence. Regarding disease-specific outcomes, at 12-month follow-up biopsy, 35% of patients had experienced persistence of prostate cancer. Of note, of the 62% of patients with GGG 2 cancer at baseline, only about 15% had persistence of disease at 12 months.
Dr. Hu pointed out that focal therapy has been adopted rapidly in areas outside of clinical trial evidence. He stressed the lack of high-quality evidence to guide patient selection for treatment, indications, and counseling about outcomes. Expert consensus must guide management and follow-up of patients receiving focal therapy until higher quality data is obtained, he urged. He reiterated that consensus has been reached that focal therapy is not appropriate for patients with low-risk prostate cancer, as it provides no benefits compared with active surveillance and is associated with significant side effects.
Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.
- Grossman DC, Curry SJ, Owens DK,et al; US Preventive Services Task Force. US Preventive Services Task Force. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;319(18):1901-1913. DOI: 10.1001/ jama.2018.3710
- Bates AS., Ayers J, Kostakopoulos N, et al. A systematic review of focal ablative therapy for clinically localised prostate cancer in comparison with standard management options: limitations of the available evidence and recommendations for clinical practice and further research. Eur Urol Oncol. 2021;4(3):405-423. DOI: 10.1016/j.euo.2020.12.008
- Azzouzi AR, Vincendeau S, Barret E, et al; PCM301 Study Group.. Padeliporfin vascular- targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial.” Lancet Oncol. 2017;18(2):181-191. DOI: 10.1016/S1470-2045(16)30661-1
- Gill IS, Azzouzi AR, Emberton M, et al; PCM301 Study Group. Randomized trial of partial gland ablation with vascular targeted phototherapy versus active surveillance for low risk prostate cancer: extended followup and analyses of effectiveness. J Urol.y 2018;200(4):786-793. DOI: 10.1016/j.juro.2018.05.121
- Albisinni S, Aoun F, Bellucci S, et al. Comparing high-intensity focal ultrasound hemiablation to robotic radical prostatectomy in the management of unilateral prostate cancer: a matched-pair analysis. J Endourol. 2017;31(1):14-19. DOI: 10.1089/end.2016.0702
- Lebastchi AH, George AK, Polascik TJ, et al. Standardized nomenclature and surveillance methodologies after focal therapy and partial gland ablation for localized prostate cancer: an international multidisciplinary consensus. Eur Urol. 2020;78(3):371-378. DOI: 10.1016/j. eururo.2020.05.018
- Klotz L, Pavlovich CP, Chin J, et al. Magnetic resonance imaging-guided transurethral ultrasound ablation of prostate cancer. J Urol. 2021;205(3):769-779. DOI: 10.1097/ JU.0000000000001362