Focal Therapy for Intermediate and High-Risk Prostate Cancer: Ready for Prime Time?
By: Bruno Nahar, MD; Dipen J. Parekh, MD | Posted on: 01 Jan 2022
Localized prostate cancer (PCa) has been traditionally managed with whole gland treatment in the form of surgery or radiation. Focal therapy (FT) has recently gained popularity as an alternative option for patients who are willing to minimize side effects common to radical treatment, such as urinary incontinence, erectile dysfunction and bowel related side effects. While prostate cancer is mostly multifocal by nature, FT relies on the concept that only some foci within the prostate drive tumor progression and risk of metastasis.1 By targeting the so-called index lesion(s) and preserving the surrounding healthy tissue, FT significantly reduces side effects with acceptable mid-term cancer control in carefully selected patients. A wide variety of energy sources are currently available, including but not limited to high intensity focused ultrasound (HIFU), cryotherapy, irreversible electroporation, focal laser ablation, photodynamic therapy and focal brachytherapy.
Patient Selection: Who Is the Ideal Candidate?
Patient selection and disease localization are essential for the success of FT. While early adopters offered FT to low-risk patients, contemporary studies have shown a shift toward the treatment of selected intermediate and high-risk patients.2 Multiparametric magnetic resonance imaging (MRI) has proven to be the best imaging modality to detect clinically significant cancer in the prostate. Moreover, MRI also allows us to perform MRI-guided biopsy of any suspicious lesion and, in combination with systematic biopsies, can significantly reduce the risk of under sampling and upgrade at radical prostatectomy.3
An International Delphi Consensus Project in 2017 recommended FT for men with low to intermediate-risk prostate cancer, including men with small volume Gleason 4+3 disease.4 A single core with small volume (≤1 mm) Gleason 3+3=6 in the untreated area is acceptable. Consensus was not reached for patients with high-risk PCa. We at our center offer FT under an institutional review board-approved protocol for carefully selected patients with high-risk PCa who have an identifiable lesion on the MRI and no more than 2 cores of Gleason 8 disease or higher (see figure).5
Current Evidence: Functional and Oncologic Outcomes
Most contemporary data on FT comes from prospective cohort studies. Among all energy sources available in FT, HIFU and cryotherapy remain the 2 most studied, yet the only randomized controlled trial (RCT) compared photodynamic therapy to active surveillance in low-risk patients. While there is robust evidence in the literature showing the benefits of FT in terms of functional outcomes, only recently mid-term data on oncologic control became available.
Guillaumier et al published the largest multisite HIFU study with the longest followup.6 They investigated 625 patients with a mean followup of 56 months, of whom 84% were intermediate or high risk. Failure-free survival (FFS) at 5 years was 88% and 84% for intermediate and high risk, respectively. Among those with high grade cancer (Gleason >8), FFS was 89% and 59% at 3 and 5 years, respectively.
Similar findings were published by Shah et al.7 The authors analyzed 122 men with intermediate (79%) and high-risk cancer (21%) who underwent cryotherapy for localized PCa. FFS at 3 years was 93.3% and 84.7% for intermediate and high-risk patients, respectively.
What if Focal Therapy Fails?
One of the main challenges in FT is followup and surveillance posttreatment. Patients should be monitored for residual cancer in the treated area and for de novo cancer in the untreated area. While prostate MRI plays an important role in diagnosing in-field recurrences and identifying new suspicious lesions, prostate biopsies are still considered the standard of care to confirm failure. Several salvage options are available. There is a general consensus that patients with low-risk cancer might be offered active surveillance, whereas definitive treatment with surgery, radiation or repeat FT is recommended for intermediate and high-risk disease. However, an important concern is whether FT compromises the quality of salvage treatment. Unfortunately, most studies on management of post-ablation failures are retrospective with small sample sizes. Nonetheless, salvage radical prostatectomy after FT appears to be safe with acceptable functional and oncologic outcomes as compared to primary treatment.8
Over the past decade, FT has been extensively studied, but more high quality evidence is needed to determine oncologic benefits over radical treatment. A well-known barrier for surgical trials is recruitment, particularly when treatments offered have markedly different outcomes, such as FT and radical prostatectomy or radiation therapy. Most ongoing RCTs are being performed in Europe, due to specific characteristics of their universal health care systems. PART (Partial Ablation Versus Radical Prostatectomy Trial) is a feasibility study that provided important insights into potential barriers of recruitment and concluded that an RCT in this setting is feasible.9 Several ongoing trials are now comparing FT to standard of care. CHRONOS is a phase 2 multi-arm study that will randomize around 1,250 patients with intermediate or high-risk cancer to either radical therapy (surgery or radiation) or FT in 1 of the study arms.10 The primary end point of the study is progression-free survival. HIFUSA is a phase 3 RCT comparing FT to active surveillance in patients with low-risk prostate cancer with a primary end point of proportion of patients who need radical therapy. FT is also being studied in patients with newly diagnosed metastatic prostate cancer as part of local cytoreductive treatment. IP2-Atlanta is a 3-arm RCT that will compare standard of care (SOC) vs FT + SOC vs radical prostatectomy or radiation therapy + SOC.
FT has emerged as a promising treatment option for men with localized PCa who are willing to preserve quality of life. Current available data show excellent functional outcomes with acceptable mid-term cancer control. However, some limitations need to be addressed before FT becomes widely available outside clinical trials. We need better imaging and navigational technology and better mapping of the PCa, to reduce both in-field and out-of-field recurrences. New technologies such as prostate specific membrane antigen positron emission tomography/computerized tomography or micro-ultrasound may help us in selecting patients who are eligible for FT.
High quality evidence and longer followup are still needed to prove oncologic efficacy. Results of ongoing trials are highly awaited and might provide more clarity on the actual role of FT in the management of PCa.
- Ahmed U: The index lesion and the origin of prostate cancer. N Engl J Med 2009; 361: 1704.
- Hopstaken JS, Bomers JGR, Sedelaar MJP et al: An updated systematic review on focal therapy in localized prostate cancer: what has changed over the past 5 years? Eur Urol 2021; https://doi.org/10.1016/j.eururo.2021.08.005.
- Ahdoot M, Wilbur AR, Reese SE et al: MRI-targeted, systematic, and combined biopsy for prostate cancer diagnosis. N Engl J Med 2020; 382: 917.
- Tay KJ, Scheltema MJ, Ahmed HU et al: Patient selection for prostate focal therapy in the era of active surveillance: an International Delphi Consensus Project. Prostate Cancer Prostatic Dis 2017; 20: 294.
- Nahar B, Bhat A, Reis IM et al: Prospective evaluation of focal high intensity focused ultrasound for localized prostate cancer. J Urol 2020; 204: 483.
- Guillaumier S, Peters M, Arya M et al: A multicentre study of 5-year outcomes following focal therapy in treating clinically significant nonmetastatic prostate cancer. Eur Urol 2018; 74: 422.
- Shah TT, Peters M, Eldred-Evans D et al: Early-medium-term outcomes of primary focal cryotherapy to treat nonmetastatic clinically significant prostate cancer from a prospective multicentre registry. Eur Urol 2019; 76: 98.
- Marra G, Valerio M, Emberton M et al: Salvage local treatments after focal therapy for prostate cancer. Eur Urol Oncol 2019; 2: 526.
- Hamdy FC, Elliott D, le Conte S et al: Partial ablation versus radical prostatectomy in intermediate-risk prostate cancer: the PART feasibility RCT. Health Technol Assess 2018; 22: 1.
- Reddy D, Shah TT, Dudderidge T et al: Comparative Healthcare Research Outcomes of Novel Surgery in prostate cancer (IP4-CHRONOS): a prospective, multi-centre therapeutic phase II parallel randomised control trial. Contemp Clin Trials 2020; 93: 105999.