Low versus high risk: the EAU analysis — The prognostic value of a biochemical recurrence following curative-intent treatment for prostate cancer was subsequently addressed in a systematic review of 77 studies conducted for the European Association of Urology (EAU) [57]. All of the 14 studies that compared biochemical recurrence versus no biochemical recurrence found biochemical recurrence to be an independent risk factor for the development of distant metastases, prostate cancer-specific mortality, and to a lesser extent, overall mortality. In the meta-analysis, among males undergoing radical prostatectomy, the main prognostic factors for distant metastases, prostate cancer-specific mortality, and overall mortality were a short PSA-DT (in most studies, < 12 months) and a pathologic Gleason score of 8 to 10. For males undergoing primary RT, the strongest prognostic factors for distant metastases, prostate cancer-specific mortality, and overall mortality were a short interval to biochemical failure (with most studies using < 18 months as the cutoff associated with an increased risk of clinical disease recurrence) and a biopsy Gleason score of 8 to 10.

These data prompted the EAU Prostate Cancer Guidelines Panel to propose a biochemical recurrence risk stratification system to predict which patients might progress after a biochemical recurrence [58]:

●Low-risk biochemical recurrence – PSA-DT >12 months and pathologic Gleason score < 8 after radical prostatectomy; interval to biochemical failure >18 months and biopsy Gleason score < 8 after RT.

●High-risk biochemical recurrence – PSA-DT ≤12 months or pathologic Gleason score ≥8 after radical prostatectomy; interval to biochemical failure ≤18 months or biopsy Gleason score ≥8 after RT.

The prognostic value of this risk grouping was externally validated in a series of 1040 males with a biochemical recurrence after radical prostatectomy [59]. After five years, metastasis-free survival was 99.7 percent in the low-risk group (95% CI 99-100 percent) and 86.7 percent in the high-risk group (95% CI 83.4-90.1 percent).

Despite the lack of prospective data validating the use of these specific risk groupings to decide whether and when to initiate salvage treatment, the EAU Prostate Cancer Guidelines Panel recommends offering close surveillance and possibly deferred salvage treatment to males with a low-risk biochemical recurrence [58]. They also recommend against offering early ADT to males with a low-risk biochemical recurrence. For a high-risk biochemical recurrence, restaging and early salvage therapy are indicated.

Clinicians still need to make individual decisions with individual patients. It is not always possible to defer initiation of salvage therapy in males with "low-risk" PSA-recurrent disease (eg, due to patient anxiety, a PSA-DT that is "close to" 12 months, or Gleason 4+3 = 7 disease rather than ≥8 on the pathology from radical prostatectomy). Careful use of intermittent ADT in males with a PSA recurrence is at least one way to balance the benefits and risks of salvage ADT.