Version May 2024
INTRODUCTION — Prostate-specific antigen (PSA) is a sensitive and specific serum marker for prostate tissue. Serial measurements are routinely obtained to detect early disease recurrence in males who have received definitive treatment for localized disease. Monitoring serum PSA frequently leads to the identification of males with a PSA-only (biochemical) recurrence. Such recurrences generally are identified before there are signs or symptoms of either locoregional recurrence or distant metastases. (See "Follow-up surveillance after definitive local treatment for prostate cancer".)
The rationale and role of diagnostic studies in males with a rising serum PSA after definitive treatment for prostate cancer are discussed here. Other related topics include the following:
●(See "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy".)
DEFINITIONS — For males who have undergone radical prostatectomy for localized prostate cancer, the most widely accepted criterion for biochemical recurrence is that of the American Urological Association (AUA) [1]. According to AUA guidelines, a biochemical recurrence is defined as a serum PSA ≥0.2 ng/mL, which is confirmed by a second determination.
By contrast, biochemical recurrence following prostate radiation therapy (RT; external beam or brachytherapy) is defined according to the Phoenix criteria [2]:
●A PSA rise of 2 ng/mL or more above the nadir PSA is considered the standard definition for biochemical failure after external beam RT, regardless of whether or not a patient receives androgen deprivation therapy.
●The date of failure is defined by the time the rise in PSA is noted.
Although an increase of 2 ng/mL or more is defined as a biochemical relapse, repeat confirmation is generally carried out to rule out a PSA bounce.
The data supporting use of these definitions are described in detail elsewhere, as are the natural history and risk stratification for males with a rising PSA after local therapy for prostate cancer. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification".)
RATIONALE FOR DIAGNOSTIC EVALUATION — A detectable rising PSA level after radical prostatectomy ≥0.2 ng/mL or a PSA rise of 2 ng/mL above the nadir level after radiation therapy (RT) may represent local, regional, and/or distant failure. The goal of the diagnostic evaluation is to identify those who are most likely to have an isolated local relapse and who thus have the greatest chance of achieving long-term disease control with additional local therapy. Osteoblastic axial skeleton metastases are the primary manifestation of widely disseminated disease, while the pelvic lymph nodes are the most common site for locoregional recurrence.
Additional aggressive local therapy may result in prolonged disease-free survival if the recurrent disease is localized, although the approach generally differs in males who have undergone radical prostatectomy versus initial RT:
●Postprostatectomy, salvage RT is associated with the best outcomes for those with a PSA ≤0.5 ng/mL. The challenge in this group is to rule out distant metastases, which is difficult at these low PSA levels. Many clinicians favor using next-generation imaging (NGI; eg, F-18 fluciclovine integrated positron emission tomography [PET]/computed tomography [CT], Axumin scan) rather than conventional bone scan and/or CT of the abdomen and pelvis once the PSA is ≥0.5 because of its greater sensitivity for detection of distant disease spread. Prostate-specific membrane antigen (PSMA) PET/CT is generally preferred over other forms of NGI because of its greater sensitivity at low PSA levels. (See 'Ga-68 and F-18 PSMA PET/CT' below and "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management".)
●Salvage local treatments that are available for patients previously treated with RT who have a PSA <10 ng/mL include salvage prostatectomy, cryotherapy, high-intensity focused ultrasound, and interstitial RT (brachytherapy). However, most males with a recurrence after RT are older and no longer candidates for salvage local therapy. In such cases, it is appropriate to be less aggressive with both imaging and therapy. Staging studies (bone scan, CT of the abdomen and pelvis) and hormonal therapy may be withheld in an asymptomatic patient until the PSA is >10 ng/mL. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer".)
For younger males who have a PSA recurrence after RT and who might be reasonable candidates for salvage local therapy, workup may be considered at a PSA level >2 ng/mL. There is no consensus as to the appropriate workup in this situation, but many clinicians, including the authors and editors associated with this review, would order multiparametric prostate magnetic resonance imaging (MRI) and perform biopsy confirmation if a potential local recurrence is found. At these low PSA levels, bone scan and CT of the abdomen and pelvis are unlikely to be revealing, and PSMA PET/CT is generally preferred for staging for distant metastases. (See "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management" and "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy".)
An important point is that among males with a rising PSA after definitive local treatment, the prolonged natural history of prostate cancer and the relatively advanced age and comorbidity often present in males with prostate cancer make the role of further treatment uncertain in many cases. An isolated biochemical recurrence may be treated with salvage local treatment, systemic therapy, or observation, depending on the site and extent of recurrent disease as established by imaging studies. Even if the site of recurrence cannot be conclusively identified, there may be a prolonged period after the documentation of a PSA recurrence before there is any clinical evidence of disease. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'Natural history after biochemical failure'.)
Consideration of clinicopathologic parameters at the time of initial treatment can help to optimize patient selection for salvage local therapy by eliminating those males who are at exceptionally high risk of systemic recurrence. As an example, following radical prostatectomy, important predictive factors for clinical recurrent disease in males with a biochemical recurrence are PSA kinetics, including time to measurable PSA, and PSA doubling time. In addition to the PSA parameters, pathologic findings at surgery (primary tumor stage, nodal and margin status, Gleason score) are also significant prognostic factors. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'Natural history after biochemical failure'.)
If such disease is suspected based on imaging studies, tissue documentation of recurrent disease should also be obtained if clinically indicated.
OUR RECOMMENDED APPROACH TO THE PATIENT — Among males considered for local salvage therapies, the most significant reason for treatment failure is undetected metastatic disease. The diagnostic workup of these patients may entail both conventional and newer imaging studies (eg, F-18 fluciclovine positron emission tomography [PET]/computed tomography [CT] or prostate-specific membrane antigen [PSMA] PET/CT) to rule out bone metastases or extensive pelvic disease.
The frequency with which unsuspected metastases are detected using conventional imaging studies (ie, bone scan, CT of the abdomen and pelvis) is very low for males with early PSA-only progression. Because of this, conventional imaging studies have often been restricted to those at highest risk for recurrence (eg, PSA levels >10 ng/mL). However, newer next-generation imaging (NGI) techniques (especially PET scanning using one of the newer prostate cancer-specific radiotracers) have improved sensitivity for disease recurrence at lower PSA levels. (See 'Next-generation imaging' below.)
Given the rapid developments in this field, consensus from expert groups as to how these tests should be integrated into the diagnostic evaluation of recurrent prostate cancer after definitive local therapy is evolving. (See 'Guidelines from expert groups' below.)
Our recommended approach to the diagnostic evaluation of males with a rising PSA after definitive local therapy for prostate cancer, which is compatible with guidelines from the National Comprehensive Cancer Network (NCCN) and the American Society of Clinical Oncology (ASCO) on use of diagnostic imaging in advanced prostate cancer, is described below. (See 'National Comprehensive Cancer Network' below and 'American Society of Clinical Oncology' below.)
Males previously treated with radical prostatectomy
●For most males with a rising serum PSA after radical prostatectomy, we do not perform any diagnostic imaging until the PSA is ≥0.5 ng/mL.
●Once the PSA is ≥0.5 ng/mL, if the patient is a candidate for local salvage therapy, we prefer next-generation imaging (NGI) over conventional imaging (ie, CT scan, bone scan) because of the greater sensitivity to detect disease both locoregionally and at distant sites. However, an important point is that, at least in the United States, NGI is not covered by many insurance companies unless bone scan and CT of the abdomen and pelvis are done first. (See 'Next-generation imaging' below.)
•PSA 0.5 to 10 ng/mL – For males with a PSA between 0.5 and 10 ng/mL, especially those with a PSA between 0.5 and 2 mg/mL, we prefer Ga-68 prostate-specific membrane antigen (PSMA) PET/CT over F-18 fluciclovine PET/CT or conventional imaging, because of the greater sensitivity at lower PSA levels. If metastases are revealed, earlier identification of a low burden of metastatic disease might influence the choice of therapy. F-18 fluciclovine PET/CT is a reasonable alternative where Ga-68 PSMA-11 is not available, but it lacks sensitivity at PSA levels <2 ng/mL. (See 'Biopsy confirmation and clarifying the extent of metastatic disease' below.)
•PSA >10 ng/mL; PSMA PET/CT unavailable or not reimbursed – If PSMA PET/CT is not available (or not reimbursed) or the PSA is >10 ng/mL, conventional imaging with bone scan and CT of the abdomen and pelvis is a reasonable first imaging strategy. If the results are negative or equivocal and there is a high suspicion for metastatic disease, a F-18 fluciclovine PET/CT can be performed.
•Biopsy confirmation of suspected metastatic disease is generally not needed unless results are equivocal. (See 'Biopsy confirmation and clarifying the extent of metastatic disease' below.)
Males with no evidence of distant metastases are appropriate candidates for referral for salvage radiation therapy (RT).
Although there is little consensus on this issue, multiparametric magnetic resonance imaging (MRI) may complement the treatment planning process by delineating the prostatic bed or localizing a small focus of locally recurrent disease in males being considered for salvage RT for an isolated prostate bed recurrence after radical prostatectomy. (See 'Postprostatectomy recurrence' below.)
The role of biopsy of the prostatic bed in patients who have undergone radical prostatectomy is controversial. The authors do not generally favor biopsy in the presence of normal rectal examination and negative imaging. (See 'Postprostatectomy recurrence' below.)
●If local therapy is not planned or is potentially inappropriate (eg, because of a short estimated life expectancy or patient preference), further diagnostic imaging may not be necessary. Conventional imaging with bone scan and CT of the abdomen and pelvis may be reasonable, although both tests are unlikely to be revealing until the PSA is >10 ng/mL. An exception is previous treatment with androgen deprivation therapy (ADT), in which case imaging tests may be positive at a lower PSA level. Biopsy is generally not needed for positive scans unless the imaging studies are equivocal.
Males previously treated with radiation therapy (including brachytherapy) — Our approach to these males sometimes differs from that of males who have previously undergone prostatectomy. Quite a number of these males are older and have comorbidities that preclude local or even systemic therapy. Many of these cases can be managed expectantly.
●Although practice is variable, for many males, we do not perform any diagnostic imaging until the PSA is ≥10 ng/mL. Although long-term outcomes are better with early treatment of PSA-only recurrence (before the PSA is >10 ng/mL) [3,4], these results may reflect the natural history of the disease rather than benefit from therapy. Males with a PSA-only relapse and relatively low PSA levels (particularly those with a low Gleason score, clinical stage T1 or T2 tumors, a long PSA doubling time, and a long interval to PSA recurrence) are more likely to have a prolonged disease course, even without treatment. The lack of randomized trials comparing surgery or other forms of local therapy with observation makes it difficult to know whether these males would have remained free of clinical metastases even without salvage therapy. (See "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy", section on 'Patient selection for local salvage therapy'.)
However, for younger males in whom local salvage therapy might be possible, we begin a diagnostic workup when the PSA rises to >2 ng/mL, ie, at the time biochemical failure is diagnosed. Many clinicians, including the authors and editors associated with this review, start with multiparametric prostate MRI to guide a confirmatory biopsy if salvage surgery/cryotherapy/brachytherapy/or high-intensity focused ultrasound are being considered. The finding of seminal vesicle invasion or extraprostatic extension on multiparametric MRI identifies males who are unlikely to achieve long-term disease control from salvage radical prostatectomy. (See 'Males previously treated with radiation therapy' below.)
If the prostate biopsy detects local recurrence, we perform diagnostic imaging to rule out concurrent metastatic disease. For males with a PSA >10 ng/mL, bone scan and CT scan are appropriate to rule out metastatic disease prior to referring the patient for local salvage treatment. If the results of conventional imaging are negative or equivocal and there is a high suspicion for metastatic disease, NGI is reasonable prior to referral for local salvage therapy. For lower PSA levels, use of NGI is preferred over conventional imaging with bone scan and CT. For most patients, PSMA PET/CT is generally preferred over other forms of imaging such as F-18 fluciclovine because of its greater sensitivity at lower PSA levels. (See 'Ga-68 and F-18 PSMA PET/CT' below.)
●For males in whom salvage local or regional therapy is not planned or is inappropriate, there is little evidence that NGI will alter treatment or prognosis. Conventional imaging with bone scan and CT of the abdomen and pelvis are appropriate in this setting to evaluate disease location and tumor burden.
ACCURACY OF INDIVIDUAL TESTS AND PROCEDURES
Evaluation for metastatic disease
Bone scan — Historically, technetium-99 radionuclide bone scan has been the most commonly used imaging procedure for the diagnosis of bone metastases in prostate cancer and remains the standard of care, despite its limited sensitivity at PSA levels <10 ng/mL [5]. In contemporary practice, in which males who have undergone treatment for localized prostate cancer are closely monitored using serum PSA, unsuspected bone metastases are only rarely detected in patients undergoing an initial evaluation for an elevated PSA, particularly after radical prostatectomy, where a diagnosis of biochemical recurrence is typically made when the PSA is >0.2 ng/mL [6-8]. (See 'Definitions' above.)
The limited yield from routine bone scan can be illustrated by a series of 239 patients in whom 414 bone scans were performed [8]. The frequency with which positive bone scans were identified increased progressively with the level of serum PSA. For patients with a PSA <10, 10 to 20, 20 to 50, and >50 ng/mL, the frequencies of positive bone scans were 4, 36, 50, and 79 percent, respectively. It should be noted that metastases in this study were identified based on a single bone scan, without confirmation by corroborative or serial imaging or confirmatory biopsy. The true metastasis rates may differ based on other factors, such as PSA doubling time, within these PSA cohorts.
For males in whom salvage therapy is being considered, the decision of whether to perform a bone scan should incorporate a consideration of the absolute level of the PSA, the time to PSA relapse, and PSA kinetics, as well as the morbidity associated with potential salvage therapy (ie, salvage radiation therapy [RT] after radical prostatectomy versus salvage radical prostatectomy after RT). Males who have a positive or suspicious bone scan are usually evaluated by targeted plain radiographs or with magnetic resonance imaging (MRI), and biopsy if radiographic findings are inconclusive. If the bone scan is negative and there is strong suspicion for bone metastases, next-generation imaging (NGI) is reasonable.
Newer imaging techniques using positron emission tomography (PET) or PET/computed tomography (CT) appear to offer improved sensitivity and specificity compared with technetium-99 radionuclide bone scans [5,9-12]. For example, in one meta-analysis, the sensitivity and specificity for radionuclide bone scanning for the detection of bone metastases were 79 and 75 percent, respectively; in contrast, the choline PET and 68-Ga prostate-specific membrane antigen (PSMA) PET had per-patient sensitivities of 91 and 93 percent, respectively, and specificities of 86 percent each for the detection of bone metastases [11]. As a result, many clinicians consider PET/CT imaging with newer isotopes to be a preferred alternative to conventional bone scan at PSA levels <10 ng/mL for males who are potential candidates for local salvage therapies. However, conventional imaging is appropriate for males who are not considered to be candidates for local salvage therapy. (See 'More sensitive prostate cancer-specific PET tracers' below.)
Guidelines from expert groups are evolving in this clinically important area. (See 'Guidelines from expert groups' below.)
Cross-sectional imaging of the pelvis and prostate bed — The sensitivity of CT to detect a pelvic recurrence appears to be limited in the setting of a PSA-only recurrence unless the PSA value is relatively high [7,13]. We do not recommend CT unless the serum PSA level is >10 ng/mL or the rate of PSA rise is >20 ng/mL per year.
This was illustrated by a study in 86 males who had undergone prostatectomy, in which CT was informative in only 12 (14 percent) [7]. The mean PSA value was significantly higher in those with a positive scan (27.4 versus 4.9 ng/mL), as was the mean PSA velocity (1.8 versus 0.7 ng/mL per month). Only eight scans (9 percent) provided new information to the clinician.
Like CT, pelvic MRI assesses nodal involvement indirectly through the use of morphology and diameter, which makes detection challenging, especially for micrometastatic disease. Reported sensitivity is <40 percent.
Standard FDG-PET — The role of standard 18-fluorodeoxyglucose (FDG)-positron emission tomography (PET) scanning in males with suspected recurrent prostate cancer is controversial [14]. While some suggest that FDG-PET is useful in imaging local recurrences [15], osseous metastases [16,17], or nodal and soft tissue lesions [16,18,19], others concluded that FDG-PET is of limited utility overall, particularly for males with a low serum PSA or PSA velocity [18,20,21]. One area where standard FDG-PET may be useful in quantification of disease burden is in males with poorly differentiated and neuroendocrine tumors [22]. (See "Chemotherapy in advanced castration-resistant prostate cancer", section on 'Aggressive prostate cancer variants'.)
Next-generation imaging
F-18 sodium fluoride PET/CT — F-18 sodium fluoride (NaF) is a bone-targeting agent that is only useful in evaluating for osseous metastases when used as a radiotracer for PET/CT. This radionuclide is US Food and Drug Administration (FDA) approved to define areas of osteoblastic activity independent of cancer type. While F-18 NaF is a more sensitive method for detection of bone metastases than radionuclide bone scan, it is not more specific. In a meta-analysis, the pooled sensitivity and specificity for F-18 NaF PET/CT were 96 and 99 percent, respectively, compared with 57 and 98 percent for conventional bone scintigraphy [23]. An important limitation of F-18 NaF PET/CT is the large number of false positive results due to benign processes such as arthritis; another is that many third-party insurers do not cover this test. (See "Bone metastases in advanced prostate cancer: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.)
More sensitive prostate cancer-specific PET tracers — FDG is excreted by the kidneys and accumulates in the bladder, which can then obscure recurrence in the prostatic bed. Early studies suggest that prostate cancer-specific tracers used for PET, such as F-18 fluciclovine, C-11 choline, and Ga-68 PSMA-11, may be better tracers than FDG for use in recurrent prostate cancer [11,12,22,24-29].
F-18 fluciclovine and F-18/C-11 choline PET/CT — Given their minimal excretion from the kidneys, F-18 fluciclovine and F-18/C-11 choline are more accurate than FDG at imaging the prostatic bed.
F-18 fluciclovine (Axumin) is an amino acid analog that has increased uptake by cancer cells. It is approved by the FDA for males with suspected prostate cancer recurrence based on elevated blood PSA levels following prior treatment. The utility of F-18 fluciclovine PET/CT has been shown in the following studies:
●In a study of 143 patients with a PSA-only recurrence who were imaged using F-18 fluciclovine, sensitivity and specificity were 91 and 40 percent, respectively; the positive predictive value (PPV) was 82 percent, and the negative predictive value (NPV) was 58 percent [30].
●In a second report of 596 males who underwent F-18 fluciclovine PET/CT after biochemical recurrence, the subject level detection rate was 68 percent (403 of 595 scans); positive findings were noted in the prostate/bed, pelvic lymph node regions, and metastatic involvement outside of the pelvis in 39, 33, and 26 percent of scans, respectively [30]. The PPV for all sampled lesions was 62 percent, and it was 92 versus 72 percent for extraprostatic and prostate/bed involvement, respectively.
●Others note a higher specificity and PPV (albeit lower sensitivity) for detecting extraprostatic rather than prostate/bed disease as well [31,32].
●A summary of sensitivity and specificity in meta-analyses for 18-F fluciclovine as compared with other prostate-specific PET tracers is provided in the table (table 1) [24]. However, sensitivity for detection of recurrent prostate cancer varies according to PSA level (table 2) [24]. Although a year 2018 consensus guideline for advanced prostate cancer suggests the use of next-generation testing with one of the more sensitive prostate cancer-specific PET tracers when the PSA is >0.5 ng/mL [33], we generally reserve the use of F-18 fluciclovine PET scanning until the PSA is at least 2 ng/mL. For males with a PSA between 0.5 and 2 ng/mL, we prefer Ga-68 PSMA-11 PET/CT over F-18 fluciclovine PET/CT because of the greater sensitivity at lower PSA levels. (See 'Ga-68 and F-18 PSMA PET/CT' below.)
●At least two clinical utility studies in Europe and the United States showed that in 60 percent or more of cases, the treating clinicians changed the patient-specific treatment plan based upon the PET findings [34,35]. However, this type of study does not address scan accuracy per se but simply how the clinicians reacted to the scan results with their patients.
●Most recently, the EMPIRE-1 trial has shown that inclusion of F-18 fluciclovine PET imaging into radiotherapy decision making and planning for males with a rising PSA postprostatectomy significantly improves outcomes from salvage RT in patients without evidence of extrapelvic disease on conventional imaging [36]. (See "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management", section on 'Salvage radiation therapy'.)
F-18/C-11 choline are PET tracers that target cell membrane lipid biosynthesis that is increased in cancer cells; C-11 choline is approved by the FDA as a radiotracer for identifying sites of disease in males with a biochemical recurrence and noninformative bone scintigraphy, CT, or MRI. Several meta-analyses have shown favorable pooled sensitivity and specificity rates with 11-choline PET/CT, both on a "per lesion" and a "per patient" basis (table 1) [24]. In one systematic review of 47 studies involving 3167 patients, performing either C-11 choline or F-18 choline PET/CT resulted in a change to the treatment plan in 41 percent of patients (381 of 983) [37].
However, as with F-18 fluciclovine, the sensitivity of C-11 and F-18 choline for detection of recurrent prostate cancer varies according to PSA level (table 2) [11,24,37,38]. F-18 choline is not available in the United States, and use of this agent for imaging is diminishing with the availability of even more sensitive PSMA-based radiotracers.
Ga-68 and F-18 PSMA PET/CT
PET scanning using novel radiotracers targeting PSMA (Ga-68 PSMA-11 [gozetotide], F-18 DCFPyL [piflufolastat F-18]) may be associated with better detection of both locoregional and distant metastatic lesions, including in males with a very low PSA level (<2 ng/mL) [12,24,39-47]:
●In a systematic review of 43 studies, the pooled detection rates for PSMA-targeted radiotracers in males with a biochemical recurrence after definitive therapy and a PSA <0.5, 0.5 to 0.9, 1 to 1.9, and ≥2 ng/mL were 45, 61, 78, and 94 percent, respectively [40]. Similar rates have been reported by others (33, 45, 59, 75, and 95 percent positive rates for PSA <0.2, 0.2 to 0.49, 0.5 to 0.99, 1 to 1.99, and >2 ng/mL, respectively) [44].
●The potential clinical impact of PSMA-based PET was addressed in a systematic review of 15 studies of Ga-68 PSMA-11 PET, totaling 1163 patients (the vast majority with biochemical failure following initial local therapy) [12]. Scan results altered management in 54 percent of cases. Among males with biochemical failure, the proportion treated with RT (from 56 to 61 percent), surgery (from 1 to 7 percent), focal therapy (from 1 to 2 percent), and multimodal treatment (from 2 to 6 percent) all increased, while that of systemic treatment (from 26 to 12 percent) or no treatment (from 14 to 11 percent) decreased with use of Ga-68 PSMA-11 PET.
●Ga-68 PSMA-11 PET/CT was directly compared with F-18 fluciclovine PET/CT in a prospective comparative trial of 50 males with an early biochemical recurrence after prostatectomy (PSA levels ranging from 0.2 to 2 ng/mL), all of whom received both tests within 15 days of each other [41]. On a per-patient basis, detection rates were significantly higher with Ga-68 PSMA-11 PET/CT than with F-18 fluciclovine (56 versus 26 percent, odds ratio 4.8 [95% CI 1.6-19.2]). For the 26 patients with a PSA concentration of 0.2 to 0.5 ng/mL, detection rates were 7 (27 percent) with F-18 fluciclovine versus 12 (46 percent) with PSMA; the corresponding values for the 18 males with a PSA concentration of 0.5 to 1 ng/mL were 5 versus 12 (28 versus 67 percent). This study was limited by the fact that the F-18 fluciclovine uptake time was shorter than that recommended by guidelines (which may have affected pelvic image quality) and the greater experience of the readers with Ga-68 PSMA-11 PET/CT (which is more frequently used in Europe).
●Compared with Ga-68, labeling of PSMA with F-18 radiotracers appears to perform similarly (even at low PSA levels [47-49]) and might offer advantages with respect to availability and image quality with regard to identifying sites of recurrence [50,51]. As an example, the diagnostic performance of piflufolastat F-18 in males with a biochemical recurrence after definitive therapy was shown in the CONDOR trial, in which 64 percent of males had a change in initial management with the addition of piflufolastat F-18 to the diagnostic imaging approach [47].
●A related agent, flotufolastat F-18 has also been studied among patients with biochemical evidence of recurrent prostate cancer, with a verified detection rate exceeding 50 percent [52].
In 2020, the FDA approved Ga-68 PSMA-11 (gozetotide) for PSMA-targeted PET imaging in males with prostate cancer, including those with a suspected recurrence based upon elevated PSA levels [53]. In 2021, largely based on the results of the CONDOR trial FDA issued an approval for piflufolastat F-18 for PSMA-targeted PET imaging in males with a suspected recurrence based upon an elevated serum PSA level after definitive local therapy [54]. In 2023, flotufolastat F-18 was FDA approved for the same indication. Both piflufolastat F-18 and flotufolastat F-18 are also approved for PSMA-targeted PET imaging in males with suspected metastases who are candidates for initial definitive therapy. (See "Initial staging and evaluation of males with newly diagnosed prostate cancer", section on 'PET imaging using PSMA-based radiotracers'.)
Despite these approvals, questions remain as to the natural history of PSMA-PET positive disease, and whether or not aggressive early therapy will improve outcomes in patients with positive PSMA imaging and negative conventional studies. Specifically, none of the trials undertaken in metastatic castration-sensitive prostate cancer have used PSMA PET imaging as an eligibility criterion; in fact, individuals with negative CT and bone scan were ineligible for all of these trials. As a result, the benefit of early rather than deferred ADT, and of adding abiraterone or enzalutamide to ADT remains unproven in the subset of males with PSMA-PET-positive but bone-scan-negative disease [55]. (See "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer", section on 'Recurrent locally advanced disease'.)
PET/MRI — Detection rates may be further improved by combining MRI and PET, which produces images with improved soft tissue (ie, lesion) contrast [56-63]. The best documented advantage is for PSMA PET/MRI. In two reports, Ga-68 PSMA-11 PET/MRI had a high detection rate for recurrent prostate cancer even at PSA levels ≤5 ng/mL [57,59]. The frequent finding of PSMA-positive lesions outside of a standard salvage RT volume (39 percent in one series [59]) could certainly alter the therapeutic plan. However, not all studies are positive [64]. Furthermore, it is not clear whether MRI and PET must be obtained simultaneously in a hybrid scanner (which is much more expensive than PET/CT scanners) or can be obtained separately as a PET/CT and dedicated MRI. This technology is not widely available.
Whole-body MRI — Whole-body diffusion-weighted MRI is an alternative next-generation imaging (NGI) strategy to PET/CT scanning using prostate cancer-specific radiotracers for detection of occult bone metastases [65-69]. In general, whole-body MRI performs better than the combination of bone scans and CT [70]; however, there are conflicting data on test performance compared with PET/CT using prostate-specific tracers [11,67,68]:
●The benefit of whole-body MRI as compared with choline PET/CT and conventional bone scan for the detection of bone metastases was addressed in a meta-analysis of 27 studies in advanced prostate cancer [11]. The pooled sensitivity and specificity rates for whole-body MRI were 97 and 95 percent, while the corresponding values for choline PET/CT were 91 and 99 percent, and for bone scan, they were 79 and 82 percent, respectively.
●The utility of whole-body MRI in detecting bone metastases in a variety of malignancies was shown in a second meta-analysis of 32 studies with 1507 patients [71]. On a per-patient basis, the pooled sensitivity and specificity rates were 95 and 92 percent; on a per-lesion basis, the corresponding values were 91 and 94 percent, respectively.
●In a subsequent prospective clinical trial in which whole-body MRI was directly compared with F-18 NaF PET/CT for the detection of bone metastases in patients with high-risk breast and prostate cancer, whole-body MRI showed similar diagnostic accuracy to NaF PET/CT and outperformed bone scan [72].
●On the other hand, at least some data in the setting of a rising serum PSA after definitive local treatment for prostate cancer suggest that whole-body MRI does not perform better than PET/CT using prostate-specific tracers. As an example, in one report of 46 males with rising PSA after prostate RT, the sensitivity, specificity, PPV, and NPV of whole-body MRI were estimated to be 45, 64, 86, and 19 percent, respectively [67]. The corresponding values for choline PET/CT were 97, 58, 93, and 78 percent, respectively.
Whole body MRI is more often used in Europe than in the United States. Nevertheless, year 2020 guidelines from the American Society of Clinical Oncology (ASCO) support the use of whole-body MRI as an alternative method for NGI for males with a rising PSA after definitive local treatment [73]. (See 'American Society of Clinical Oncology' below.)
Biopsy confirmation and clarifying the extent of metastatic disease — Biopsy confirmation is generally not needed if metastatic disease is suspected based on initial imaging. If results are equivocal on conventional imaging, we would pursue NGI. (See 'Next-generation imaging' above.)
For males with positive results on conventional imaging, the role of NGI (PET/CT or PET/MRI using one of the prostate-specific radiotracers, or whole-body MRI) is unclear. The ASCO guidelines suggest NGI could be used to clarify the burden of disease if it might potentially shift treatment intent from multimodality management of oligometastatic disease to systemic anticancer therapy, alone or in combination with targeted therapy for palliative purposes [73], but prospective data are limited, and this is a controversial area. (See 'American Society of Clinical Oncology' below and "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer", section on 'Metastasis-directed therapy for oligometastatic disease'.)
Prostate evaluation
Multiparametric prostate MRI — Multiparametric MRI of the prostate is often used in the setting of biochemical failure after definitive therapy to identify residual disease or locoregional recurrences, as well as to plan local salvage therapy.
Males previously treated with radiation therapy — For males with a biochemical recurrence following initial RT, MRI has been used to identify recurrent disease in the prostate, and the presence of seminal vesicle invasion or extraprostatic extension in those who are considered candidates for salvage prostatectomy [74-76]. The presence of these features (particularly seminal vesicle invasion) identifies males who are unlikely to achieve long-term disease control from salvage radical prostatectomy. (See "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy" and "The role of magnetic resonance imaging in prostate cancer", section on 'Suspected local recurrence after prostate radiation therapy'.)
However, there are only limited data on the accuracy of MRI in males with previously irradiated prostate glands [75-79]. One series included 45 consecutive males who underwent salvage radical prostatectomy for biopsy-proven locally recurrent prostate cancer over a six-year period, all of whom underwent endorectal coil MRI prior to surgery [75]. All scans were read independently by two experienced radiologists. There was significant variation between readers, with a sensitivity for seminal vesicle involvement of 38 and 62 percent, respectively.
Relapse after RT is commonly located close to the original tumor [80]. RT causes significant changes in the prostate (atrophy, fibrosis, thickening of the perirectal fascia, increased signal intensity of pelvic musculature) [81]. Neoplastic tissue is characterized by early contrast enhancement, whereas irradiated noncancerous tissue presents with low or late enhancement. Contrast-enhanced multiparametric MRI has excellent sensitivity and specificity in this setting (95 and 89 percent, respectively).
Postprostatectomy recurrence — Although there is less consensus on this issue, some radiation oncologists use multiparametric MRI to complement the treatment planning process by delineating the prostatic bed or localizing a small focus of locally recurrent disease in males undergoing salvage RT for an isolated prostate bed recurrence after radical prostatectomy.
On multiparametric MRI, locally recurrent prostate cancer after radical prostatectomy can be recognized as any soft tissue mass in the surgical bed with a higher T2 signal intensity than the adjacent muscle, restricted diffusion, and rapid wash-in and wash-out after contrast injection. Several studies have shown the utility of MRI for the detection of locally recurrent prostate cancer following radical prostatectomy, with a specificity and accuracy of over 90 percent; however, the average PSA level in these studies was >0.5 ng/mL [82,83]. Only a few studies have suggested benefit for MRI in identifying early recurrence with a lower PSA level, with at least one suggesting a sensitivity of 86 percent in this setting [84,85].
Role of transrectal ultrasound-guided prostate biopsy
Males previously treated with radiation therapy — Prostate biopsy may provide useful information to aid in early diagnosis of a local recurrence in males with a rising PSA following RT [86]. However, there are important caveats to its use. The histologic regression of tumor cells after RT may be prolonged; a positive result fewer than two years after treatment does not correlate well with disease progression.
For males with a biochemical recurrence, transrectal ultrasound (TRUS), with TRUS-guided biopsy, may have a role in localizing the site of recurrence and guiding secondary treatment decisions. The positive predictive value (PPV) of TRUS in this setting ranges from 50 to 95 percent in various studies [87-89]. However, the true sensitivity of TRUS-guided biopsy cannot be assessed since there is no "gold standard" by which to determine the false negative rate with biopsies.
An American Society for Radiation Oncology (ASTRO) consensus panel recommended that routine prostate biopsy for evaluation of a PSA recurrence after RT not be performed unless salvage prostatectomy or another local salvage procedure is being considered [90]. In this setting, TRUS-guided biopsy is indicated for histologic confirmation of a suspected isolated local recurrence prior to salvage therapy. In such cases, a biopsy should be performed no sooner than 18 months after completion of RT.
However, many clinicians, including the authors and editors associated with this review, prefer multiparametric prostate MRI to guide a confirmatory biopsy if salvage surgery/cryotherapy/brachytherapy/or high-intensity focused ultrasound are being considered. The finding of seminal vesicle invasion or extraprostatic extension on multiparametric MRI identifies males who are unlikely to achieve long-term disease control from salvage radical prostatectomy. (See 'Males previously treated with radiation therapy (including brachytherapy)' above.)
Postprostatectomy recurrence — The authors do not generally favor TRUS-guided prostate bed biopsy in the presence of normal rectal examination.
The value of TRUS biopsy for males with a rising serum PSA after radical prostatectomy and negative evaluation for distant metastases is controversial [87,91-93]. The largest retrospective experience with biopsy in this setting consists of 114 patients who underwent 156 TRUS biopsies at the University of California, San Francisco (UCSF) [91]. In this series, 61 males (54 percent) had a biopsy-confirmed local recurrence, two-thirds of which were at the anastomotic site. In one-third of cases, more than one biopsy was required.
Other data suggest value for digital rectal examination (DRE) in selecting males with a rising PSA for confirmatory TRUS-guided biopsy. In a series of 62 TRUS biopsies performed on 41 males with a serum PSA ≥0.4 ng/mL following radical prostatectomy, local recurrence was confirmed in 39 and 59 percent after one or more biopsies, respectively [92]. The biopsy was more likely to be positive in males with a palpable lesion compared with those with a normal DRE and TRUS (78 versus 23 percent). These authors concluded that routine TRUS-guided anastomotic biopsy is not indicated in males with a normal DRE and TRUS.
GUIDELINES FROM EXPERT GROUPS — There is no consensus as to the appropriate sequence of diagnostic imaging in the setting of a rising PSA after definitive local therapy. Recommendations are available from several groups. Links to additional society guidelines can be found elsewhere. (See 'Society guideline links' below.)
National Comprehensive Cancer Network — Guidelines for diagnostic imaging in males with a biochemical recurrence following local therapy from the National Comprehensive Cancer Network (NCCN) are based on prior treatment and life expectance [94]:
●If the patient has a life expectancy >5 years:
•Risk stratification using PSA doubling time is recommended to inform counseling or nomogram use (postradiation recurrence); for patients with a suspected recurrence following surgery, decipher molecular assay can be considered to inform counseling.
•In either case, workup for progression should include bone and soft tissue evaluation. Bone imaging can be achieved by conventional technetium-99m-MDP bone scan. Plain films, CT, MRI, or PET/CT or PET/MRI with F-18 sodium fluoride, C-11 choline, or F-18 fluciclovine, Ga-68 PSMA-11, or F-18 piflufolastat PSMA can be considered for equivocal results on initial bone imaging. Soft tissue imaging of the pelvis, abdomen, and chest can include chest CT and abdominal/pelvic CT or abdominal/pelvic MRI. Alternatively, Ga-68 PSMA-11 or F-18 piflufolastat PSMA PET/CT or PET/MRI can be considered for bone and soft tissue (full body) imaging.
•Because of the increased sensitivity and specificity of PSMA-PET tracers for detecting micrometastatic disease compared with conventional imaging (CT, MRI) at both initial staging and biochemical recurrence, the panel does not feel that conventional imaging is a necessary prerequisite to PSMA-PET and that PSMA-PET/CT or PSMA-PET/MRI can serve as an equally effective, if not more effective front-line imaging tool for these patients.
●If the patient has a life expectancy ≤5 years:
•Observation with monitoring with the expectation to deliver palliative therapy for the development of symptoms or a change in exam or PSA that suggests symptoms are imminent.
•Workup at the time of progression should include bone and soft tissue evaluation. Bone imaging can be achieved by conventional technetium-99m-MDP bone scan. Plain films, CT, MRI, or PET/CT or PET/MRI with F-18 sodium fluoride, C-11 choline, F-18 fluciclovine, Ga-68 PSMA-11, or F-18 piflufolastat PSMA can be considered for equivocal results on initial bone imaging. Soft tissue imaging of the pelvis, abdomen, and chest can include chest CT and abdominal/pelvic CT or abdominal/pelvic MRI. Alternatively, Ga-68 PSMA-11 or F-18 piflufolastat PSMA PET/CT or PET/MRI can be considered for bone and soft tissue (full body) imaging.
American Society of Clinical Oncology — Recommendations from a year 2020 guideline from the American Society of Clinical Oncology (ASCO; with panel representation from the American College of Radiology [ACR], American Urological Association [AUA], and the Society of Urologic Oncology [SUO]) for optimum imaging strategies for males with a rising serum PSA after treatment of localized prostate cancer are outlined in the table (table 3) [73]. Like the NCCN, these guidelines advocate the use of NGI only after negative conventional imaging if salvage therapy is being considered. They do not address different diagnostic approaches based on the level of the PSA. Their suggested imaging approach in this setting is provided in the algorithm (algorithm 1).
European Association of Urology — The following recommendations for restaging in males with a rising PSA after local therapy for prostate cancer are from a 2018 guideline from the European Association of Urology (EAU) [95]:
●For PSA relapse following radical prostatectomy, consider bone scan and abdominopelvic CT scans only for males who have a high baseline PSA (>10 ng/mL) or high PSA kinetics (PSA doubling time <6 months) or in those with symptomatic bone disease. Although sensitivity is low when the PSA is <1 ng/mL, choline PET/CT may be helpful for selecting patients for salvage therapy, particularly if the PSA doubling time is <6 months.
●For males with a biochemical recurrence after RT, biopsy status is a major predictor of outcomes, provided the biopsies are performed 18 to 24 months after treatment. Histologic proof of local recurrence is necessary before treating the patient. Multiparametric MRI can be used for biopsy targeting and guidance of local salvage treatment. Detection of local recurrence is also feasible with choline and acetate PET/CT but PET/CT has poorer spatial resolution than MRI. There are no specific recommendations for evaluating for bone metastases in this group.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis and management of prostate cancer".)
SUMMARY AND RECOMMENDATIONS
●Definition and rationale for diagnostic evaluation
•A detectable rising prostate-specific antigen (PSA) level after radical prostatectomy (≥0.2 ng/mL), or a PSA rise of 2 ng/mL above the nadir level after radiation therapy (RT) may represent local and/or distant failure, for which additional therapy may be warranted.
•The goal of the pretreatment evaluation for males who meet these criteria is to identify those who are most likely to have an isolated local relapse and who thus have the greatest chance of long-term disease control with additional local therapy. (See 'Rationale for diagnostic evaluation' above.)
-For males who have previously undergone radical prostatectomy, salvage RT is associated with the best outcomes for those with a PSA ≤0.5 ng/mL. The challenge in this group is to rule out distant metastases, which is difficult at these low PSA levels.
-For patients previously treated with RT, options for salvage local therapy include prostatectomy, cryotherapy, high-intensity focused ultrasound, and interstitial RT (brachytherapy). However, most males are older and no longer candidates for salvage local therapy. In such cases, it is appropriate to be less aggressive with both imaging and therapy. Staging studies (next generation imaging with PSMA PET scanning, bone scan, CT of the abdomen and pelvis) and hormonal therapy may be withheld in an asymptomatic patient until the PSA is >10 ng/mL. For selected younger males who have a PSA recurrence after RT and who might be reasonable candidates for salvage local therapy, workup may be considered at a PSA level >2 ng/mL.
●Diagnostic evaluation – Our recommended approach to the diagnostic evaluation of males with a rising PSA after definitive local therapy for prostate cancer is summarized below, and differs according to whether initial treatment was radical prostatectomy or radiotherapy (including brachytherapy). (See 'Our recommended approach to the patient' above.)
●Patients previously treated with prostatectomy
•Timing – For most males, we do not perform any diagnostic imaging until the PSA is ≥0.5 ng/mL. Once the PSA is ≥0.5 ng/mL, imaging to evaluate for distant metastases is appropriate. Males with no evidence of distant metastases are appropriate candidates for referral for salvage radiation therapy (RT).
•Potential candidate for local therapy – In general, if the patient is a potential candidate for local salvage therapy, we prefer next-generation imaging (NGI; eg, PET using PSMA-targeted radionuclides) over conventional imaging (ie, CT scan, bone scan) because of the greater sensitivity to detect disease both locoregionally and at distant sites. However, NGI may not be covered by insurance companies unless bone scan and CT of the abdomen and pelvis have been performed first, although this is changing. (See 'Next-generation imaging' above.)
-PSA 0.5 to 10 ng/mL – For males with a PSA between 0.5 and 10 ng/mL, especially those with a PSA between 0.5 and 2 ng/mL, we prefer a prostate-specific membrane antigen (PSMA)-based radiotracer (ie,Ga-68 PSMA-11 or piflufolastat F-18) for PET/CT over F-18 fluciclovine PET/CT or conventional imaging because of the greater sensitivity at lower PSA levels. If metastases are revealed, earlier identification of a low burden of metastatic disease might influence the choice of therapy. F-18 fluciclovine PET/CT is a reasonable alternative where a PSMA-targeted radiotracer is not available, although sensitivity is very limited at PSA levels 0.5 to 2 ng/mL (table 2). (See 'Biopsy confirmation and clarifying the extent of metastatic disease' above.)
-PSA >10 ng/mL; PSMA-PET/CT unavailable or not reimbursed – If PSMA PET/CT is not available (or not reimbursed) or the PSA is >10 ng/mL, conventional imaging with bone scan and CT of the abdomen and pelvis is a reasonable first imaging strategy. If the results are negative or equivocal and there is a high suspicion for metastatic disease, a F-18 fluciclovine PET/CT is recommended. Biopsy confirmation of metastatic disease is generally not needed unless results are equivocal. (See 'Biopsy confirmation and clarifying the extent of metastatic disease' above.)
•Role of prostate biopsy and imaging – The role of biopsy of the prostatic bed in patients who have undergone radical prostatectomy is controversial. The authors do not generally favor biopsy in the presence of normal rectal examination. (See 'Role of transrectal ultrasound-guided prostate biopsy' above.)
Although there is little consensus on this issue, multiparametric prostate MRI may complement the treatment planning process by delineating the prostatic bed or localizing a small focus of locally recurrent disease in males who are being considered for salvage RT for an isolated prostate bed recurrence after radical prostatectomy. (See 'Multiparametric prostate MRI' above.)
•Local therapy not planned – If local therapy is not planned or is potentially inappropriate (eg, because of a short estimated life expectancy or patient preference), conventional imaging with bone scan and CT of the abdomen and pelvis is reasonable, although these two tests are unlikely to be revealing until the PSA is >10 ng/mL (unless they have had prior androgen deprivation therapy [ADT], in which case imaging tests may be positive at a lower PSA level). Further diagnostic imaging may not be necessary. (See 'Evaluation for metastatic disease' above.)
●Patients previously treated with radiation – Our approach to these patients sometimes differs from that of individuals who have previously undergone prostatectomy. Many of these individuals are older or have more comorbidities and may no longer be candidates for local or even systemic therapy. Many of these cases can be managed expectantly.
•Timing of diagnostic evaluation – Although practice is variable, for many patients, we do not perform any diagnostic imaging until the PSA is ≥10 ng/mL. Patients with a PSA-only relapse and relatively low PSA levels (particularly those with a low Gleason score, clinical stage T1 or T2 tumors, a long PSA doubling time, and a long interval to PSA recurrence) are more likely to have a prolonged disease course, even without treatment. The lack of randomized trials comparing surgery or other forms of local therapy with observation makes it difficult to know whether these males would have remained free of clinical metastases even without salvage therapy. (See "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy", section on 'Patient selection for local salvage therapy'.)
•Choice of modality
-For males in whom salvage local or regional therapy is not planned or is inappropriate, there is little evidence that NGI will alter treatment or prognosis. Conventional imaging with bone scan and CT of the abdomen and pelvis are appropriate in this setting to evaluate disease location and tumor burden. (See 'Evaluation for metastatic disease' above.)
-However, for younger males in whom local salvage therapy might be possible, we begin a diagnostic workup when the PSA rises to >2 ng/mL, ie, at the time biochemical failure is diagnosed.
In this setting, many clinicians, including the authors and editors associated with this review, start with multiparametric prostate MRI to guide a confirmatory biopsy if salvage surgery/cryotherapy/brachytherapy/or high-intensity focused ultrasound are being considered. The finding of seminal vesicle invasion or extraprostatic extension on multiparametric MRI identifies males who are unlikely to achieve long-term disease control from salvage radical prostatectomy. (See 'Males previously treated with radiation therapy' above.)
If the prostate biopsy detects local recurrence, we perform diagnostic imaging to rule out concurrent metastatic disease. For males with a PSA >10 ng/mL, bone scan and CT scan are appropriate to rule out metastatic disease prior to referring the patient for local salvage treatment. If the results of conventional imaging are negative or equivocal and there is a high suspicion for metastatic disease, a PET/CT scan is reasonable prior to referral for local salvage therapy. For PSA levels <10 ng/mL, use of a PSMA-targeted radiotracer (Ga-68 PSMA-11 or piflufolastat F-18) for PET/CT is generally preferred over conventional imaging with CT or bone scan or F-18 fluciclovine PET/CT because of the greater sensitivity at lower PSA levels. F-18 fluciclovine PET/CT is a reasonable alternative where a PSMA-targeted radiotracer is not available. (See 'Ga-68 and F-18 PSMA PET/CT' above and 'F-18 fluciclovine and F-18/C-11 choline PET/CT' above.)
ACKNOWLEDGMENT — We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate gratefully acknowledges Dr. Vogelzang's role as Section Editor on this topic, and his dedicated and longstanding involvement with the UpToDate program.
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