Despite advances in imaging-based diagnostic pathway, which can localize cancers more accurately, patients with localized disease are usually managed with whole gland radiation or prostatectomy. Whilst we can argue about the exact rates, it is irrefutable that such radical approaches confer high rates of genitourinary side effects, and in the case of radiotherapy, rectal toxicity. Indeed, urinary incontinence requiring one or more pads in 10%-20%, impotence in 30%-60% and radiotherapy related rectal side effects (bleeding, discomfort, loose stools) in 5%-10% (moderate to severe).¹ To reinforce this, it is rather sobering that multiple studies such as SPCG-4, PROTECT, PIVOT, and PREDICT have shown cancer-specific mortality absolute risk reduction no higher than about 5% for those high-grade cancers. For instance, the PREDICT risk calculator shows that, the absolute survival advantage from whole-gland therapy, over active monitoring, for a patient with intermediate risk prostate cancer (PSA 6, T2, G4 + 3) is 3% at 10 years and 5% at 15 years. With this in mind, the COMPARE study showed that most patients, on average, are willing to accept a trade-off in survival for functional preservation.

Data from focal therapy is now starting to show that many patients who need treatment do not need to make that trade-off, and can treat the cancer effectively with a 5- to 10-fold relative risk reduction in side effects.

Through the seismic change we have witnessed in the diagnostic pathway, a change from a rather random diagnostic strategy to one that is accurately targeted to areas of likely cancer alongside a recognition that whilst multifocal cancer exists (not only in prostate, of course) most patients have one index lesion that drives the progression of the cancer.^2-4 Numerous groups have conducted a phased program of health technology evaluation of the concept of focal therapy.^5-7 These early studies and subsequent data have consistently shown that when delivered in a focal manner, incontinence rates of 1%-2% and erectile dysfunction in 5%-20% are achievable, with rectal toxicity being rare. The question has always remained about medium- and long-term cancer control.

At AUA2022, we presented the UK’s long-term cancer control outcomes of 1,379 patients who underwent treatment with focal high intensity focused ultrasound (HIFU; Sonablate) across 13 UK sites since 2005. Whilst many have criticized focal therapy for treating men with low-risk disease that are eminently suitable for active surveillance (often forgetting that they themselves have removed or irradiated thousands of prostate with low-risk cancer), it is worth noting that 93% of patients in this focal HIFU series had D’Amico intermediate or high-risk localized disease (79% had Grade Group ≥2). Patients were given up to two focal HIFU sessions if required. Reassuringly, we demonstrated a 7-year failure-free survival (a composite of transition to whole-gland, third focal, metastases, or cancer-specific death), of 69%, with only 0.5% serious adverse events. No statistically significant differences in failure-free survival (FFS) were observed between patients with intermediate vs high-risk disease, although lower FFS was observed in patients with Grade G roup 3 disease compared to those with Grade Group 2. Seven-year metastases and cancer-specific survival was 100% (99%-100%).

It is recognized that randomized comparative data are often called for but worth noting that other urological innovations have been adopted on a wholesale basis before the randomized control trial (RCT) was reported. RCTs evaluating focal HIFU against whole gland treatments have been difficult to deliver largely due a lack of patient equipoise. Is it reasonable for us to continue waiting for an RCT which would deny many thousands of men a year a treatment option which has a better therapeutic ratio that whole-gland options?^8-10 What attempts have so far been made for delivery of RCTs?

The Partial Ablation Versus Radical Prostatectomy in Intermediate-Risk Prostate Cancer (PART) trial reported successful recruitment to the pilot study evaluating focal HIFU against radical prostatectomy, albeit with a longer accrual window than anticipated and a lowering of the initial target. Worryingly, 9/41 (22%) of those allocated radical and 1/41 (2%) of those allocated focal HIFU declined their allocated treatment, resulting in an overall compliance rate of 75.6% (31/41) and 92.7% (38/41), respectively. The Qualitative Research Integrated Within Trials (QuinteT) sub-study determined the lack of equipoise towards randomization and institutional difficulties as barriers to recruitment.¹⁰ The Focal Prostate Ablation Versus Radical Prostatectomy (FARP) trial recruited 118 patients, but also encountered high rates of rejection following randomization, with 22/62 patients allocated to radical prostatectomy rejecting this treatment. The investigators report a compliance rate of 80% (94/118). Most recently, Imperial Prostate 4-CHRONOS (IP4-CHRONOS) reported at ASCO 2022 that direct randomization to radical therapy or focal therapy was not feasible, due to lack of equipoise, while randomization to focal therapy with or without neoadjuvant treatment was feasible.⁹ IP4-CHRONOS-A recruited 36 patients, following randomization to radical treatment 4/18 withdrew consent, while no patients randomized to focal therapy declined treatment (Figure 1). Overall compliance rate was 81% (29/64). IP4-CHRONOS-B recruited 64 patients, all patients were compliant to focal and neoadjuvant treatment (Figure 2).

As a less robust alternative to RCTs, propensity score-matched studies have been performed. Shah et al demonstrated that if focal therapy using HIFU or cryotherapy were compared to laparoscopic prostatectomy, there were no statistically or clinically significant differences in FFS at 8 years.¹¹ van Son et al further compared radical therapies (radical prostatectomy and radical radiotherapy) and focal therapies (brachytherapy, HIFU, and cryotherapy).¹² This analysis reported radical radiotherapy had statistically significant better FFS although attribution from those patients with a biochemical recurrence managed with watchful waiting strategy likely account for this difference. Added to the fact that patients receiving external beam radiation therapy experienced lower overall survival than after radical prostatectomy or focal therapy, indicates the weaknesses of propensity matched analyses like these where residual confounders are problematic.

Our data adds to the evidence base for focal HIFU as a treatment option for patients with localized, clinically significant prostate cancer. In the absence of a completed randomized control trial reporting outcomes following focal therapy, these results can be used to counsel patients according to possible oncological outcome and support clinicians in determining which patients may benefit from focal HIFU. It is also time that guideline committees noted this updated evidence, the clear problems of funding and delivering an RCT, and the patient perspective, so that a shift towards advocating focal therapy in select cases, treated within prospective registries, can be made.