**11. Approach to a patient with a rising PSA after radiotherapy**

Following definitive therapy for prostate adenocarcinoma, the NCCN recommends obtaining a PSA every 6–12 months for 5 years, and then annually thereafter [8]. As well, a PSA may be obtained as frequently as every 3 months to clarify disease status in certain cases, especially for patients with aggressive disease. PSA failure postradiotherapy is defined by the Phoenix Consensus as a PSA increase by 2 ng/mL or more above the nadir. A work-up for recurrence can begin prior to reaching nadir +2 ng/mL, especially for candidates for salvage treatments with long life expectancies, and if there is a rapid increase in the PSA. However, it is important to note that many patients do experience 1–2 PSA upward "bounces" that resolve. There are data demonstrating that a PSA nadir >0.5 ng/mL is associated with lower rates of biochemical control, distant metastasis-free survival, prostate cancer specific survival, and OS [48].

Work-up in the setting of current or impending biochemical failure includes PSMA imaging, MRI-prostate, and testosterone. Prostate biopsy is required for confirmation of recurrence, especially if local salvage therapy (e.g., high-dose rate [HDR] brachytherapy, low-dose rate [HDR] brachytherapy, SBRT, radical prostatectomy, high intensity focused ultrasound, or cryotherapy) is desired.

NRG Oncology/RTOG 0526 prospectively analyzed patients who had prior EBRT and experienced local failure, and were treated with salvage LDR [49]. This study included patients treated with EBRT for low- or intermediate-risk prostate adenocarcinoma with EBRT and biopsy-proven local failure >30 months after definitive treatment. Inclusion criteria also included PSA <10 ng/mL, and no regional/distant disease. Between May 2007–January 2014, 20 centers administered salvage treatment to 100 patients, of whom 92 patients were analyzable. The median prior EBRT dose was 74 Gy, and median follow-up was 6.7 years, with LDR administered at a median time of 85 months after EBRT. ADT was combined with salvage radiotherapy for only 16% of patients. Ten-year OS was 70%, with disease-free survival of 61% at 5 years and 33% at 10 years; of note, local failure was rare at 5% at 10 years.

A meta-analysis was performed of salvage treatments after definitive radiotherapy, consisting of 150 studies, seeking to compare the efficacy and toxicity of the six techniques listed above (HDR, LDR, SBRT, radical prostatectomy, high intensity focused ultrasound, and cryotherapy) [50]. HDR brachytherapy and SBRT had the highest rates of adjusted 5-year recurrence free-survival at 60%, while cryotherapy

had the lowest at 50%. CTCAE grade ≥ 3 GU toxicity was the lowest for SBRT at 4.2%, and the highest for HIFU at 23%; as well, CTCAE grade ≥ 3 GI toxicity was the lowest for SBRT and HDR at 0.0%, and the highest for radical prostatectomy at 1.9%. From this retrospective meta-analysis, the authors concluded that the radiotherapy techniques appeared most effective in reducing recurrence and limiting severe GU toxicity; severe GI toxicity remained low regardless of technique.
