From the above findings, it could be argued that evidence should be adequate to provide clinicians with established recommendations for the clinical practice.

We therefore examined available guidelines in order to search for established recommendations concerning the use of PSA for either the prediction or management of metastatic prostate cancer. In the context of a broader project aimed at updating the synopsis of existing recommendations on tumor markers in solid tumors [16], we set up a search strategy and explored the following databases: Pubmed-Medline, National Guideline Clearinghouse (NGC) and GIN library; we also interrogated 11 websites of scientific societies producing guidelines and 61 websites of medical scientific societies [16]. The search was conducted in the last 5 years and sorted 96 documents identified as guidelines concerning prostate cancer, which were further examined and selected on the basis of the methodological quality and rate of utilization by clinicians in Italy. The methodological quality was evaluated according to inclusion criteria set by National Guideline Clearinghouse, and documents were selected if the clinical practice guideline was based on a systematic review and a description of the search strategy was reported. Widely used guidelines were considered also when methodology was not fully compliant with above mentioned criteria. A total of 35 guidelines concerning prostate cancer were eventually selected. The recommendations concerning the use of PSA in the different clinical settings were extracted and synoptically presented.

In this clinical setting, PSA may provide information on both long-term outcomes – such as biochemical recurrence, clinical recurrence, and survival – and the risk that occult bone metastases may be already present at the time of first diagnosis. Table 4.2 summarizes the recommendations of the examined guidelines.

Six clinical practice guidelines recommend the use of PSA to categorize patients into risk groups [17–22]; all of them recommend to use the D’Amico risk criterion [11], in which PSA is used in association with Gleason score and clinical stage. More complex algorithms are mentioned by some guidelines [21, 24–26], but no specific approaches are suggested in the recommendations other than the D’Amico risk criterion.

Five clinical practice guidelines consider the risk of metastatic spread in newly diagnosed patients with apparently locoregional disease and conclude that bone scan positivity is expected to be extremely low (<1 %) in low-risk patients with PSA values ≤10 ng/mL [18, 21–24]. As a result, all the five examined guidelines state that imaging staging (CT and bone scan) should be considered in patients with a PSA level >20 ng/mL prior to treatment.

The natural history of prostate cancer is characteristically long, and recurrence may occur years after the treatment of the primary tumor with curative intent. In the long term, a significant percentage of patients – from 11 to 40 % according to different studies – will eventually develop recurrent disease [27–29]. Bone metastases represent the predominant site of distant recurrence in patients with prostate cancer, occurring in a high percentage of patients as unique site of metastatic spread [30].

Given its excellent characteristics of sensitivity and specificity, PSA is the tool of choice for the routine monitoring of patients with prostate cancer treated with curative intent, in order to detect early disease recurrence. However, just thanks to its elevated sensitivity, PSA may become detectable years before the occurrence of clinical signs of disease progression. The occurrence of detectable PSA values in many patients, without overt signs of regional or distant progressive disease after initial therapy with curative intent, leads to identify a new clinical scenario, labeled as biochemical recurrence or PSA recurrence. It has been estimated that approximately 35–50 % of patients will experience a PSA recurrence within 10 years after radical prostatectomy or radiation therapy [31]. The time between PSA recurrence and the occurrence metastatic disease is variable and in general extended, with a reported median time of 8 years [32]. Frequently androgen deprivation therapy (ADT) is prescribed before metastases appear, and many patients with PSA recurrence after primary therapy receive ADT [33–35]. Men developing PSA progression while receiving ADT are considered castration-resistant prostate cancer (CRPC), and those cases in which metastases are undetectable by imaging are labeled as nonmetastatic CRPC (M0-CRPC). It has been reported that approximately 10–20 % of patients, without evidence of metastases and treated with ADT, will eventually develop CRPC within approximately 5 years [33]. CRPC is a further step in the progression of prostate cancer toward clinically evident disseminated disease; 33 % of CRPC patients have been shown to develop bone metastases within 2 years [33], and different studies report a median survival from CRPC diagnosis ranging from 9 to 30 months [36].

The follow-up after the treatment of the primary tumor with curative intent is a manifold scenario in which variations of clinical conditions over time induce different clinical questions. The key point is to offer appropriate treatment options to each individual patients, weighing the benefit of supplying potential life prolonging therapies to patients with aggressive prostate cancer and the risk of over-treating men with indolent disease.

During this long-lasting time period after radical treatment of primary prostate cancer, the questions facing both the clinician and patient are as follows: When PSA reliably indicates the biochemical recurrence? Which is the risk of clinical progression after the biochemical recurrence in patients either on ADT or in the CRPC phase?