Most of the 270,000 men who will be diagnosed with prostate cancer in the next year will have localized disease,¹ where curative intent treatment is appropriate and guideline concordant.² Of those men electing treatment, approximately 40%–50% chose radiation as a first line of therapy.³ Unfortunately, there is no perfect treatment, and therefore a proportion of these men will suffer biochemical relapse (prostate specific antigen 2 ng/ml over the nadir) and will be faced with the tough decisions that surround radio-recurrent prostate cancer. For these men, the options are generally observation, androgen deprivation therapy or salvage with curative intent. This article will review the guideline-concordant options and outcomes for those men who elect salvage with curative intent.

For men electing or considering salvage therapy with curative intent, assurance of local recurrence is paramount. As stipulated by the NCCN (National Comprehensive Cancer Network^®)² and EAU (European Association of Urology)⁴ guidelines, men should undergo soft tissue imaging to rule out metastatic disease. Currently available prostate specific positron emission tomography scans yield the highest sensitivity and should be preferred (such as prostate-specific membrane antigen, fluciclovine F-18, choline etc) over conventional axial imaging (Fig. 1). For those men without evidence of metastasis on axial imaging, a local assessment with prostate biopsy is necessary to ensure histological evidence of locally recurrent disease. At our center (and as supported by the NCCN and EAU guidelines), we advocate magnetic resonance imaging prior to prostate biopsy in these men to provide additional local staging and treatment planning, and to optimize detection of histological recurrence (Fig. 2).^2,4 Without these assurances, men may be inappropriately subjected to treatments that carry significant quality of life burden (“First, do no harm”). Additionally, men considering salvage therapy who are candidates by virtue of this evaluation should be counseled on the latency of prostate cancer—where biochemical recurrence often precedes metastatic progression by many years—and the competing risks of noncancer mortality in a shared decision-making approach. Assuming a negative metastatic workup, histological confirmation of local disease and an acceptance of the competing risks, guideline-supported salvage options include radical prostatectomy, re-irradiation, cryotherapy and high intensity focused ultrasound (HIFU). Nonguideline-supported therapies will not be discussed and should not be considered outside of a clinical trial.

Salvage radical prostatectomy (sRP) is the therapy with the largest body of evidence supporting its use in locally radio-recurrent prostate cancer. In a recent meta-analysis of 2,323 patients, sRP was associated with a 34%–83% 5-year biochemical control rate and a cancer-specific survival of 72%–83% at 10 years.⁵ However, sRP carries a significant quality of life burden including incontinence (>1 pad/day: 23%–73%) and erectile dysfunction (87%–100%).⁵ Numerous approaches have been described, including open versus robotic, anterior versus space of Retzius sparing, and nonnerve sparing versus nerve sparing, with varying impacts on quality of life and risk of complications. Regardless of approach, these surgeries are complex by virtue of the prior radiation exposure and represent the final curative intent local therapy option for these men, so the decision to proceed and choice of approach should be based on the goals of oncologic control. As such, efforts to maximize quality of life (eg nerve sparing or space of Retzius sparing) should only be employed if there is no anticipated reduction in oncologic control (eg nonnerve sparing in the setting of cT3a disease or anterior approaches in the setting of anterior tumors). Finally, it is important to note that some men elect radiation for primary therapy as a result of an underlying rationale to avoid surgery (comorbidity, intolerance of surgical risk, side effect avoidance), and these underlying factors are likely still present and need to be addressed prior to considering a surgical salvage.

For men who are unable/unwilling to accept a surgical approach, nonsurgical options include re-irradiation, cryotherapy and HIFU. Re-irradiation can be performed with either stereotactic body radiotherapy (SBRT), low-dose rate brachytherapy (LDR-BT) or high-dose rate brachytherapy (HDR-BT). While brachytherapy techniques require well-trained high-volume brachytherapists, SBRT is more widely available. In a recent retrospective assessment of SBRT including 100 men, SBRT biochemical control rates were 55% at 3 years, with 20% of men reporting grade 2 or greater genitourinary/gastrointestinal toxicity,⁶ rates comparable to those reported for HDR-BT and LDR-BT. Salvage whole gland cryotherapy has been evaluated in retrospective series with variably reported biochemical control rates. However, whole salvage therapy has a high rate of complication, with urinary incontinence, obstructive urinary symptoms and impotence reported by ˜70% of men.⁷ Focal cryoablation has been studied with lower risks of side effect, but higher risk of recurrence. HIFU is a relatively new ablative therapy in the management of radio-recurrent prostate cancer. When given in this setting (as a focal treatment), ˜50% of men achieve biochemical control (3-year data).⁸ Side effects include urinary tract obstruction, urinary tract infection and fistula.

As would be expected, there are no high-quality head-to-head comparisons of these techniques to guide decision making. However, a recent meta-analysis evaluated these salvage therapies for radio-recurrent prostate cancer in over 11,000 men treated for local recurrence.⁹ Adjusted biochemical control rates at 5 years were not statistically different between sRP, re-irradiation (SBRT, LDR-BT and HDR-BT), cryotherapy and HIFU at 50%–60%. Despite the similar reported outcomes, the definition of recurrence varies between modalities, making such comparisons difficult to interpret and biased toward nonsurgical salvage. Again, and while recognizing the inherent detection biases due to differing definitions of control that might influence the biochemical control rate, such analyses affirm these guideline-supported options as reasonable salvage treatments.

In conclusion, a significant number of men will be faced with the challenging decision of how to manage their recurrent prostate cancer after radiation therapy. For men electing salvage intervention and in whom appropriate workup confirms histologically localized recurrence, options include salvage surgery, re-irradiation, cryotherapy and HIFU, with biochemical success rates ranging between 50% and 60% but varying degrees of side effect burden. As urologists, we must be prepared to appropriately evaluate these men and discuss the relative strengths and weaknesses with each salvage approach to provide high-quality patient-centered care.