Our management and definition of clinically significant prostate cancer have evolved over the past 2 decades. At 15 years, survival rates are similar between primary surveillance and radical treatment for prostate cancer, furthering the questions, “Who benefits from treatment?” and “How best to treat?” Evidence supporting the efficacy of focal ablation for primary treatment of prostate cancer has dramatically expanded, and practice patterns are shifting to be more inclusive of these modalities. In the salvage setting, a similar paradigm shift is emerging in the literature as well.

Management of localized recurrence after primary radiotherapy (RT) for prostate cancer is challenging. Approximately 30% of patients with prostate cancer undergo primary RT. Among these, 10% to 30% experience a treatment failure, of whom 10% to 30% present at a clinically localized stage.^1,2

Options for management of localized recurrence include watchful waiting, androgen deprivation therapy, salvage radical prostatectomy (RP), salvage radiation, and salvage focal ablation. At present, 90% to 95% of men with a biochemical recurrence (BCR) after primary RT are managed with androgen deprivation therapy alone.³ Reasons contributing to this practice include that this cohort is typically older and at higher risk for surgical intervention, the limited availability of urologists who perform salvage RP, and the relatively poor functional outcomes associated with whole-gland (namely, salvage RP) salvage treatment.

Local failure after primary RT is significantly associated with poorer overall survival, prostate-cancer specific survival, and distant metastasis–free survival.⁴ Identification of patients who will benefit from treatment with curative intent of localized recurrences requires an individualized approach, augmented by high-quality imaging (prostate-specific membrane antigen [PSMA] positron emission tomography [PET] and MRI of the prostate) and template biopsy. For these patients, AUA and National Comprehensive Cancer Network guidelines suggest consideration of RP, cryotherapy, high-intensity focused ultrasound (HIFU), or re-irradiation, although the guidelines do not comment on the extent to which ablation should be performed.

In the salvage setting, advances in PSMA PET imaging have enhanced our ability to identify localized recurrences after primary RT with 27% higher accuracy compared to traditional CT/bone scan.⁵ As a parallel to primary focal ablation, salvage focal ablation has emerged in the literature as an alternative to whole-gland treatment. The concept of the index lesion in the recurrent setting has been demonstrated by multiple studies. Marra et al reviewed 41 whole-mount prostate specimens after salvage RP and determined that 56% were appropriate candidates for focal ablation based on tumor volume and mapping.³ Chesnut et al reviewed tumor maps, MRI data, and biopsy data for 216 cases after salvage RP and concluded that 27% were eligible for salvage focal ablation, identifying an index lesion in many cases.⁶

The majority of the literature evaluating outcomes after ablation for localized recurrences has included whole-gland therapies, namely cryotherapy and HIFU. Indeed, one of the largest systematic reviews on outcomes after salvage treatment for prostate cancer, the MASTER study, included 150 studies.⁷ Most interestingly, there was no difference in recurrence-free survival rates between any of the treatment modalities—including HIFU and cryotherapy—at 5 years post intervention. A more recent systematic review analyzed outcomes after both focal and whole-gland salvage cryotherapy and HIFU.⁸ Studies are few, but BCR rates were equivalent between the focal and whole-gland cryotherapy cohorts at 2 and 5 years, and salvage focal HIFU demonstrated a BCR rate of 52% at 3 years. These findings are similar to those reported in the MASTER study.

Additionally, a propensity-matched score analysis of salvage RP vs salvage HIFU/cryotherapy in 444 localized recurrences demonstrated a trend toward lower rates of metastases at 6 years in the ablation arm.⁹ This has been proposed to be related to an abscopal effect, wherein delivering ablative energy to the primary tumor may confer a distant therapeutic effect on cancer-containing (or at-risk) cells. Mouse models of transplanted prostate cancer cells (Yang et al, 2019) have demonstrated this phenomenon, and a protective immuno-modulatory response to irreversible electroporation has also recently been reported (IRE),¹⁰ suggesting potential systemic or distant therapeutic benefits of a local ablative treatment. As data emerge in this space, the role of both primary and salvage focal ablation will likely continue to expand.

An even more compelling argument for salvage focal ablation over salvage RP derives from functional outcomes. When comparing salvage RP, cryotherapy, and HIFU, rates of severe incontinence were highest after salvage RP and lowest after focal salvage cryotherapy in one study evaluating salvage focal HIFU.⁷ Rates of erectile dysfunction are largely similar after all modalities given a very high prevalence at baseline prior to intervention.

Overall, the available data on outcomes after salvage ablation for prostate cancer remain limited and must be considered with the following 2 caveats. Most available literature has included whole-gland ablation, and furthermore, many studies were conducted prior to the era of advanced MRI and PSMA PET imaging, which may confound initial patient selection. Despite this, the few studies reporting on focal salvage ablation show promising and equivalent oncologic outcomes at 3 (HIFU) and 5 (cryotherapy) years to salvage RP with a favorable functional outcome.

Patient selection, technique, and experience all contribute to a successful outcome when treating recurrent prostate cancer. With equivalent 5-year BCR rates after all salvage treatment modalities, delivering a more targeted ablation when feasible based on biopsy and imaging may confer a similar oncologic outcome with a more favorable side-effect profile. Ongoing studies will help to further develop this challenging aspect of the prostate cancer continuum.