In the current issue of Prostate Cancer Prostatic Diseases, Szymaniak and colleagues from UCSF present long term oncologic outcomes of patients who presented a non-detectable PSA after radical prostatectomy and then experienced biochemical recurrence (BCR), defined here as two consecutive PSA ≥0.03 ng/ml, at least 6 months after surgery (REF). In a large contemporary cohort of 3348 men, the authors identified 642 patients exhibiting such characteristic; the study then gives the readers a clear picture of the long-term outcomes of these patients, reporting an excellent metastatic free survival (MFS) rate of 92%, prostate cancer specific mortality (PCSM) of 3% and all-cause mortality (ACM) of 6% at ten years. Not surprisingly, the patients experiencing BCR had more aggressive PCa features, globally expressed by a higher CAPRA and CAPRA-S score. Of note, across the 642 patients experiencing BCR after a negative post-op PSA, 46% received salvage therapy, with PSA doubling time <6mo, elevated CAPRA-S score and higher Decipher score being significantly associated to receiving salvage therapy on multivariable cox regression. The patients that did receive salvage therapy, mainly by radiotherapy ± ADT, exhibited worst MFS (86% vs 97%), worst PCSM (5% vs 1%) and a similar ACM (7% vs 5%) compared to patients not receiving salvage therapy, confirming the intrinsic differences across these two patient groups.

We commend the investigators for the precision in the follow-up, for the long-term data and for the rigorous methodology of the UCSF Urologic Outcomes Database, allowing such elegant studies. The presented results should prompt some reflection:

First, considering a PSA value of ≥0.03 ng/ml as BCR is subject to debate. Current guidelines recommend withholding any salvage treatment after surgery before PSA has reached a value of 0.20-0.40 ng/ml [1]. There is great variability in PSA testing kits: [2] as such, PSA velocity or doubling time interpretation at such low values must be cautious. The authors report a median PSA at treatment of 0.08 ng/ml, which is way lower than that supported by the EAU or established in recent RCTs as RADICALS or RAVES trials [3]. Considering that roughly 50% of patients may increase their PSA after surgery, yet never reach the critical value of 0.20 ng/ml [4], triggering treatment before such threshold may determine overtreatment.

On the other hand, the present data confirm that the outcomes of patients receiving salvage therapy are excellent [5], with 5% PCSM at 10 years from surgery. Again, these patients were treated at low PSA values and this remains a crucial variable in determining outcome of salvage therapy [6, 7]. We are witnessing the rise of next generation imaging, with PSMA PET/CT on the rise, especially in the setting of recurrent disease [8]. The data of the present manuscript highlight the need to administer salvage therapy at low PSA threshold and avoid waiting time for PSA to rise and eventually obtain a positive PSMA scan. Especially for these patients who had an initial negative PSA after surgery, the information needed to trigger and plan salvage therapy is already there, on the pathologic specimen analysis and clinical characteristics before surgery [9]. At PSA levels <0.20 ng/ml, nomograms and clinical reflection are probably superior to next generation imaging. We must understand cancer biology rather than just irradiate the pelvis when PSA rises: the data presented by the authors confirms that the timing of BCR is different in different types of PCa. As such, also the prescription of Next Generation Imaging should be judicious and done when results are likely to modify our clinical strategy.

The long-term data presented by the authors must also remember us that PCa is a slowly progressing disease and that only a third of patients with BCR will progress to metastatic disease: [10] across the 642 patients studied, 38% did not receive salvage therapy and in this group PCSM was only 1%. Each patient requires personalized care and therapy must be administered if life expectancy is adequate. Geriatric evaluation is paramount and as ACM remains superior to PCSM, for some patient the best treatment is no treatment.

“When managing prostate cancer (PCa), one should never rush” used to say Professor Miano, former chair of the Urology department of the University of Rome. Recurrent PCa, especially after an initial PSA drop <0.03 ng/ml after radical prostatectomy, is a slowly progressing disease. If treated adequately, patients can also be cured: a true rarity in surgical oncology. We must take the time to study and understand cancer biology, obtain the necessary information from the cancer and the patient, and be able to deliver the correct salvage therapy timely, yet with no rush.