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. (See "Follow-up surveillance after definitive local treatment for prostate cancer".)
Monitoring serum PSA after treatment of localized stage prostate cancer 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.
The definition of PSA-only recurrence after treatment of clinically localized prostate cancer, its natural history, and risk stratification of these patients will be reviewed here. The diagnostic evaluation and management approaches for such patients are discussed elsewhere:
●(See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation".)
●(See "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy".)
DEFINITION OF BIOCHEMICAL PROGRESSION — The definition of PSA-only recurrence depends upon the initial treatment. Notably, these definitions were derived in an era where radiographic restaging consisted of radionuclide bone scans and computed tomography (CT) scans. They are likely to evolve with the emergence of positron emission tomography (PET) scanning using more sensitive prostate-specific radiotracers as a replacement for bone scan and CT scans. At many institutions, virtually all patients with a biochemical recurrence after definitive local therapy get a PET scan and this has resulted in a smaller pool of patients defined as having an isolated biochemical recurrence. (See 'Integration of PET scanning' below and "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'More sensitive prostate cancer-specific PET tracers'.)
After radical prostatectomy — All prostate tissue is removed during a successful radical prostatectomy. Postoperatively, detectable serum PSA using standard immunoassays is indicative of residual prostatic tissue, which presumably represents locoregional or systemic cancer [1].
Whether such disease is locally confined to the pelvis or represents systemic metastases is an important distinction with significant implications for patient management. If the serum PSA never falls to undetectable levels or is rising rapidly, systemic disease is more likely than residual disease in the prostatic bed [2,3]. By contrast, if the PSA gradually rises after remaining undetectable for two or more years, an isolated local recurrence in the prostatic bed is more likely [3,4]. (See "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management".)
For patients who have undergone radical prostatectomy, the most widely accepted criterion for biochemical recurrence is that of the American Urological Association (AUA) [5]. According to AUA guidelines, a biochemical recurrence is defined as a serum PSA ≥0.2 ng/mL, which is confirmed by a second determination with a PSA ≥0.2 ng/mL.
Benign PSA rise after radical prostatectomy — Not uncommonly (5 to 15 percent of patients), patients can develop a slowly rising PSA that does not represent prostate cancer recurrence. This is due to a small amount of residual noncancerous prostate tissue remaining in situ after surgery and slowly growing to produce a small quantity of PSA that becomes detectable in the blood. However, a PSA level of 0.4 ng/mL or higher after successful radical prostatectomy is highly concerning for recurrent disease; patients with a persistent or rising PSA at this level should be considered for adjunctive therapy, generally radiation therapy to the prostatic bed. (See "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management".)
In the "modern era" of "more strategic," "less radical" nerve-sparing, bladder neck-sparing, and distal urethral-sparing open or robotic radical prostatectomy, the phenomenon of a detectable but benign PSA rise should not be ignored, especially in the setting of organ-confined or lower-grade cancer. While we do not want to delay potentially curative prostate bed radiation therapy (RT) for PSA recurrence, it may be better to follow the PSA in these equivocal cases to be more sure of a true cancer recurrence before initiation of salvage therapy.
After radiation therapy — The definition of biochemical failure is complicated after RT, whether given by external beam techniques, brachytherapy, or a combination. Some normal prostatic glandular tissue remains and serum PSA levels are unlikely to fall to undetectable levels following a course of RT. The interpretation of serum PSA levels is also complicated in some patients with intermediate or high risk disease by the use of androgen deprivation therapy (ADT), which can suppress serum PSA.
Meeting criteria for biochemical relapse based upon fulfilling criteria for a biochemical failure does not necessarily mandate treatment.
Effect of radiation therapy on PSA — The decline in serum PSA following RT (without ADT) is gradual and the mean time for the PSA to reach its nadir is 18 months or longer [6]. The rate of decline in the serum PSA does not appear to correlate with the risk of subsequent disease relapse. PSA is usually measured every three to six months following RT.
The nadir of the serum PSA concentration (ie, the lowest level to which it drops) is a strong indicator of treatment success following RT [7-11]. Although lower nadir values are associated with improved outcomes, no absolute level can distinguish treatment success from treatment failure [6]. A consensus panel convened by the American Society for Radiation Oncology (ASTRO) in 1996 recommended that the nadir PSA value be considered a prognostic factor similar to pretreatment variables such as serum PSA, Gleason score, and clinical tumor (T) stage [12].
Males whose serum PSA becomes undetectable (ie, <0.1 ng/mL) after receiving a full course of RT seem to have more durable responses than those who do not. Relative stability of the PSA nadir is important, since a rising serum PSA probably indicates recurrence.
Models have been developed to predict the future risk of a clinical relapse after RT in individual patients, based upon pretreatment variables, the RT dose, and the results of post-treatment serum PSA levels, but they are not yet available for clinical use [13].
Phoenix criteria — A second consensus conference was held by ASTRO in 2005 to address issues that had been identified in the application of the 1996 definition of PSA failure [14]. These Phoenix criteria replaced the earlier ASTRO criteria.
PSA failure was defined in the revised "Phoenix" criteria as follows:
●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 Phoenix criteria were initially developed for external beam radiation therapy only. However, the same definition is generally used for patients treated with brachytherapy.
PSA bounce — Serum PSA levels typically fall after RT and can then rise ("bounce") transiently, at a median of 12 to 18 months after treatment [15]. This PSA bounce can occur in the absence of recurrent disease and does not necessarily signify a treatment failure or constitute an indication for therapeutic intervention. There are no definitive methods to distinguish a PSA bounce from recurrent cancer.
If an increase in serum PSA is observed, the patient should be given reassurance, and the PSA can be repeated in three to six months. If serum PSA continues to increase, a repeat biopsy can be considered, although the interpretation of a prostate biopsy performed following RT is difficult.
The PSA bounce phenomenon has been observed after low-dose rate brachytherapy [16], high-dose rate brachytherapy [17,18], and external beam RT [19,20]. The frequency with which such PSA bounces are observed varies, depending upon the definition used [16,19].
The most extensive data on the PSA bounce phenomenon come from a consecutive series of 820 patients treated with low-dose rate brachytherapy [21]. The incidence of PSA bounce decreased with an increasing threshold to define a PSA bounce (30, 20, 13, and 10 percent, respectively, using definitions of 0.2, 0.4, 0.6, and 0.8 ng/mL). Regardless of the definition used, PSA bounces occurred significantly earlier compared with biochemical failure, as defined by a PSA rise >2 ng/mL above nadir (15 to 17 versus 34 months).
The clinical implications of a PSA bounce are uncertain. Although some studies have shown an improved prognosis in patients who experience a PSA bounce [21-24], other studies have reported in a worse prognosis in this setting [25,26].
PREDICTING BIOCHEMICAL FAILURE — A variety of factors have been evaluated in an attempt to identify males at high risk of disease recurrence following radical prostatectomy or radiation therapy (RT). In multivariate models, the most important determinants of outcome are the pretreatment serum PSA and Gleason score, as well as the anatomic extent of disease. (See "Initial staging and evaluation of males with newly diagnosed prostate cancer".)
Most PSA recurrences are diagnosed early, but the time to PSA recurrence can be variable. In a series of 4561 males who had undergone radical prostatectomy, 31 percent eventually developed a PSA recurrence [27]. Of these, approximately 90 percent occurred within the first five years. Patients with a pretreatment PSA <10 ng/mL and those with a Gleason score <7 were more likely to have a delayed recurrence.
Increasingly, models or nomograms have been developed to predict individualized estimates of biochemical recurrence after definitive local therapy of prostate cancer. Some are based only on pretreatment factors, while others incorporate the pathologic examination of the surgical specimen and, in one case, the duration of time that a man has remained free of progression since surgery. These approaches are discussed elsewhere. (See "Follow-up surveillance after definitive local treatment for prostate cancer", section on 'Risk of recurrence and timing'.)
Multiple molecular prognostic tests are emerging, specifically with an aim to better risk stratify males treated for localized prostate cancer. The role of these tests in males who have undergone definitive treatment for prostate cancer remains controversial. (See "Molecular prognostic tests for prostate cancer".)
NATURAL HISTORY AFTER BIOCHEMICAL FAILURE — A PSA relapse does not necessarily predict the development of metastases or death from prostate cancer [28-31]. In many cases, the natural history of disease is very prolonged, and this should be considered in deciding whether or not treatment is indicated.
Risk of metastases or death — The risk factors for disease progression can be illustrated by two large series, one in males treated with surgery and the other with external beam radiation therapy (RT):
●Radical prostatectomy – The prolonged natural history following biochemical recurrence is illustrated by a series of 1973 males treated with radical prostatectomy at Johns Hopkins between 1981 and 2010 who did not receive adjuvant hormonal therapy or androgen deprivation therapy (ADT) prior to documented distant metastasis, 315 of whom developed a biochemical recurrence (PSA ≥0.2 ng/mL) [29]. At a median follow-up of eight years, 134 patients (30 percent) had developed metastases, and the median metastasis-free survival was 10 years. In a multivariate analysis, independent factors associated with the development of metastases were PSA doubling time (PSA-DT; <3 versus 3 to 8.9 versus 9 to 14.9 versus ≥15 months) and the Gleason score from the radical prostatectomy specimen (≤6 versus 7 versus 8 to 10).
A later analysis of a larger cohort from this same institution (450 males with a biochemical recurrence after radical prostatectomy who did not receive adjuvant or salvage therapy before the development of metastatic disease) provided information about 5- and 10-year metastasis-free survival, stratified by pathologic Gleason score and PSA-DT [29]. A more clinically useful table combining Gleason score and PSA-DT was presented by this group in 2003 based on 312 men, but it was never published (table 1) [32]. A comparable table to estimate the 10-year risk of prostate cancer-related death in males with a rising PSA after radical prostatectomy, based on 379 such males derived from the same institution, was published in 2005 (table 2) [28].
A subsequent report from this group focused on 656 males from two independent cohorts who had a biochemical relapse following surgery and a short PSA-DT of <12 months [33]. The analysis used the most recent PSA value within a window of 6 to 18 months prior to the diagnosis of first metastasis and only included males who did not receive neoadjuvant, adjuvant, or salvage hormone therapy or RT. In multivariate analysis adjusted by surgical year, site, age, race, pathologic T stage, Gleason score, surgical margin status, and PSA-DT, a PSA value ≥0.5 ng/mL independently predicted for the development of metastatic disease. Among males with a PSA-DT <12 months, those with a low PSA level (<0.5 ng/mL) had excellent distant metastasis-free survival through year 15 (≥90 percent), while metastasis-free survival at year 5 and beyond was only approximately 20 percent for those with a baseline PSA ≥0.5 ng/mL. These data suggest that the addition of absolute PSA level can better define an "at-risk" population with a short PSA-DT.
A nomogram has been developed for predicting prostate cancer-specific mortality for males with a biochemical recurrence after radical prostatectomy that is based on preoperative PSA, pathologic Gleason score, extraprostatic extension, seminal vesicle invasion, time to biochemical recurrence, the PSA level at biochemical recurrence, and PSA-DT [34]. This nomogram is available online.
●Radiation therapy – A retrospective analysis of 2694 males with localized prostate cancer treated with external beam RT illustrate the natural history after treatment with external beam RT [35]. With a median follow-up of 83 months, 609 males experienced biochemical failure, based upon the Phoenix criteria. Following biochemical failure, the median time to the development of metastases was 5.4 years, and the median time to prostate cancer-specific mortality was 10.5 years. Factors associated with a worse prognosis included a higher initial clinical tumor stage, shorter PSA-DT, Gleason score, and a shorter interval from initial treatment to biochemical recurrence.
Among men undergoing definitive RT for high and intermediate-risk prostate cancer, approximately 10 percent will develop a local recurrence, which is a risk factor for further disease progression and death, especially in those with high-risk disease [36]. However, the majority of patients who develop distant metastases (80 percent in this pooled analysis of data from 12,533 patients enrolled on 18 randomized trials) do not have a detectable local recurrence preceding it.
Specific prognostic factors — Several parameters (eg, PSA-DT, Gleason score, PSA response to salvage ADT) may be used to distinguish males who are likely to develop "clinically significant" disease from those who have more indolent disease after biochemical relapse [28,29]. This information can be an important factor in determining whether and when to initiate further treatment.
The same features that predict biochemical failure after initial treatment for prostate cancer provide insight into the likely natural history of the disease following biochemical recurrence [37,38]. These include the clinicopathologic features at original presentation (tumor [T] stage, PSA level, PSA velocity, biopsy Gleason score) as well as pathologic findings at the time of prostatectomy for males who have undergone surgery (T stage, nodal and margin status, and Gleason score), and the presence of a local failure. As such, these features can aid in deciding when and how to treat males with a rising PSA after local treatment. (See 'Predicting biochemical failure' above.)
As examples:
●Males who have short intervals to PSA failure and rapid PSA-DT after prostatectomy or RT have significantly increased rates of distant metastases [28,37,39,40]. (See 'Risk of metastases or death' above.)
●In several studies, the presence of lymph node or seminal vesicle involvement with tumor, or Gleason score ≥8 disease at the time of initial prostatectomy predict for occult distant metastatic disease, and are associated with poor salvage rates with local-only salvage therapy [4,41-46].
●Combining post-treatment PSA kinetics and the pathologic findings from prostatectomy can further optimize appropriate patient selection for salvage local therapy by eliminating those males who are at exceptionally high risk of systemic recurrence. In one study, investigators constructed a flow diagram to predict four-year actuarial progression-free probabilities after salvage RT (figure 1) [44]. Males with Gleason score ≥8 and a pre-RT PSA ≥2 ng/mL had the worst four-year progression-free survival probability (12 percent), while those with Gleason scores of ≤7, pre-RT PSA <2 ng/mL, positive surgical margins, and a PSA-DT >10 months had the highest (77 percent).
●The importance of local failure after RT for high-risk prostate cancer was noted in an individual patient-level meta-analysis of six trials of definitive RT for aggressive prostate cancer [47]. All patients included in the analysis had both an elevated tendency to develop early distant metastases and an elevated chance of having occult micrometastatic disease at presentation. Yet, overall, males who developed a local failure had a significantly greater hazard of distant metastases or death compared with those who did not (HR 2.46 [95% CI 1.22-4.93], p = 0.01).
PSA doubling time and Gleason score — Multiple studies indicate that the PSA-DT can be predictive of both clinical metastasis-free survival and prostate cancer-specific mortality in males with a rising serum PSA after radical prostatectomy [39,48-53]. The PSA-DT has not been validated after brachytherapy [54].
The prognostic significance of PSA-DT is illustrated by the largest series, which studied the outcomes in 8669 males with clinically localized or locally advanced nonmetastatic prostate cancer [50]. Of these men, 5918 initially were treated surgically and 2751 were managed with RT. Males with a PSA-DT of <3 months had a 20-fold increased risk of dying of prostate cancer compared with those with a PSA-DT of ≥3 months (table 3).
A later analysis found that the use of the Gleason score in conjunction with PSA-DT provided a better estimate of prostate cancer-specific mortality in males with a rising PSA following RT [39].
●For males with a PSA-DT <3 months, prostate cancer-specific mortality rates five years after biochemical failure were 35 and 75 percent with Gleason scores of ≤7 and ≥8, respectively.
●For males with PSA-DT ≥3 months, the five-year prostate cancer-specific mortality rates for Gleason score ≤7 and ≥8 disease were 4 and 15 percent, respectively.
These data support the view that males who have a short PSA-DT and a Gleason score ≥8 disease are at particularly high risk of dying from prostate cancer and are unlikely to achieve long-term disease control from local-only salvage therapies.
However, the number of males with a PSA-DT <3 months was relatively small. Among those who have a biochemical recurrence with a somewhat longer PSA-DT, prostate cancer is still a major cause of mortality. In one study of males with a rising PSA following prostatectomy and a PSA-DT <15 months, prostate cancer accounted for approximately 90 percent of all deaths by 15 years after biochemical recurrence [48]. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'When to initiate ADT-based therapy'.)
Caution should be exercised when an ultrasensitive PSA assay is used to calculate the PSA-DT. The studies that demonstrated the importance of PSA-DT were based upon calculations when level of detectability of the serum PSA was ≥0.2 ng/mL. Ultrasensitive PSA assays have a lower limit of detection of 0.01 ng/mL or less, and PSA-DTs using such an assay for the first detection of PSA following treatment correlate poorly with the older methodology [55].
PSA "response" to androgen deprivation therapy — The "PSA response" to ADT following biochemical recurrence may be useful as an intermediate end point for prognosis and to predict the time to prostate cancer death in males with biochemical recurrence following radical prostatectomy or RT.
Males with a rapid rise in PSA prior to salvage hormonal therapy or a slow decline after treatment are likely to have tumor that is not responsive to salvage hormonal therapy [56]. By contrast, those with a more rapid rate of post-therapy PSA decline or a more protracted rise in pre-salvage therapy PSA had more favorable outcomes. Neither the post-therapy rate of PSA decline by itself, nor the PSA-DT, nor the timing of salvage hormone therapy predicted for the time to prostate cancer-specific death following salvage hormone therapy.
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. (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".)
Integration of PET scanning — The emergence and increasing availability of positron emission tomography (PET) scanning using more sensitive prostate cancer-specific radiotracers such as F-18 fluciclovine or one targeting prostate-specific membrane antigen (PSMA; such as Ga-68 PSMA-11 or F-18 DCFPyL) to replace radionuclide bone scan and computed tomography scanning has markedly changed the landscape of diagnosis and treatment of biochemically recurrent prostate cancer, as only those patients with negative PET scans are considered "true biochemical recurrences." However, whether all PET positive patients with a biochemical recurrence have a worse prognosis compared with those who are PET-negative, and whether they should be managed like traditional metastatic disease is not clear, and will require prospective study.
At least some data suggest that males with a rising PSA after radical prostatectomy who are selected for salvage RT based upon PET with a PSMA-specific radiotracer have better outcomes than do those who are selected for salvage RT using only conventional radiographic studies. (See "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management", section on 'Patients selected using prostate-specific PET radiotracers'.)
Molecular prognostic tests — Advances over the last decade have dramatically increased both our understanding of prostate cancer biology and our ability to obtain molecular information from small amounts of prostate tissue. Along with these advances have come newly available and emerging tissue-based prostate cancer biomarker tests, which promise to help determine prostate cancer prognosis as well as guide treatment (table 4). Several of these, including the Oncotype DX Genomic Prostate Score (GPS) and the Decipher Genomic Classifier (GC) have shown some utility for prognostication following radical prostatectomy, and in some cases, in males with biochemically recurrent disease after radical prostatectomy.
The potential utility of this approach was shown in an ancillary study of the RTOG 9601 trial, a double-blind trial of males receiving salvage RT that demonstrated the superiority of two years of bicalutamide over placebo in conjunction with prostate bed RT. (See "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management", section on 'Prostate bed RT plus androgen deprivation therapy'.)
GC scores were generated from 486 of the 760 randomized patients, and 352 that passed microarray quality control comprised the final cohort for analysis [60]. On multivariate post-hoc analysis, after adjusting for age, race/ethnicity, Gleason score, T-stage, margin status, PSA level at trial entry, and treatment arm, the GC was independently associated with distant metastases (HR 1.17, 95% CI 1.05-1.32) and prostate cancer-specific mortality (HR 1.39, 95% CI 1.20-1.63). Although the planned original analysis was not powered to detect a significant treatment interaction by GC score, low GC scores were also associated with less benefit from the addition of bicalutamide to salvage RT.
This trial and the subject of the clinical utility of molecular prognostic tests in prostate cancer is discussed in more detail elsewhere. (See "Molecular prognostic tests for prostate cancer", section on 'Genomic classifier (Decipher)'.)
DIAGNOSIS AND TREATMENT — The variable natural history for males with a PSA-only recurrence following definitive therapy for localized prostate cancer needs to be integrated into the decision of when and how to proceed with restaging and treatment. In addition to prognostic factors such as the recurrence-free interval and the PSA doubling time, other factors that should be considered include the patient's age and life expectancy, associated comorbidities, and psychological factors [61]. (See 'Risk of metastases or death' above.)
An important point is that the likely natural history, which is based on specific prognostic factors, should be considered before instituting an extensive workup to discover metastatic disease. Once the PSA goes over the recurrence threshold of >0.2 ng/mL, many clinicians immediately order a positron emission tomography (PET) scan using one of the more sensitive radiotracers without giving much thought to whether the patient has high- or low-risk disease. We discourage this practice, and urge clinicians to apply risk stratification (for example, the low- versus high-risk classification proposed by the European Association of Urology) to decision making about both the diagnostic evaluation and treatment. (See 'Low versus high risk: the EAU analysis' above.)
Nevertheless, at several institutions, virtually all patients with a biochemical recurrence get a PET scan. Where available, we use PET-positive versus PET-negative status as well as risk grouping based on PSA doubling time and Gleason score to stratify likely prognosis and the need for treatment. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'More sensitive prostate cancer-specific PET tracers'.)
The approach to treatment for individuals with a rising PSA after definitive local treatment are discussed separately:
●(See "Rising serum PSA after radiation therapy for localized prostate cancer: Salvage local therapy".)
SUMMARY
●Definition of biochemical progression
•Prostate-specific antigen (PSA) is a sensitive and specific marker for prostate cancer. Monitoring PSA after treatment of localized prostate cancer leads to the identification of males with a PSA-only (biochemical) recurrence when there are no symptoms or signs of locally recurrent or metastatic disease.
•The definition of a PSA-only recurrence has historically been based upon the initial treatment received by the patient:
-For patients who have undergone radical prostatectomy, the American Urologic Association (AUA) defines biochemical recurrence as a serum PSA ≥0.2 ng/mL, which is confirmed by a second determination with a PSA ≥0.2 ng/mL. (See 'After radical prostatectomy' above.)
-For patients initially treated with external beam radiation therapy, the American Society for Radiation Oncology (ASTRO) has developed the Phoenix criteria, which define PSA recurrence as a PSA rise of 2 ng/mL or more above the nadir PSA, 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 the Phoenix criteria were initially developed for external beam radiation therapy only, the same definition is used for patients treated with brachytherapy. (See 'Phoenix criteria' above.)
These definitions were derived in an era where the diagnostic evaluation consisted predominantly of radionuclide bone scanning and computed tomography (CT) scanning. They are likely to evolve with the emergence and increasing use of positron emission tomography (PET) scanning using more sensitive prostate-specific radiotracers as a replacement for bone scan and CT scans. At most institutions, virtually all patients with a biochemical recurrence after definitive local therapy get a PET scan and this has resulted in a smaller pool of patients defined as having a truly "isolated" biochemical recurrence. (See 'Integration of PET scanning' above.)
●Natural history of biochemical relapse
•The natural history of disease for males with a PSA-only (biochemical) recurrence is often very prolonged. A biochemical recurrence does not necessarily predict the subsequent development of metastatic disease, and it is not necessarily an indication for systemic treatment. The indications and role of systemic therapy are discussed separately. (See 'Risk of metastases or death' above and "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'Overview of the general approach'.)
•Various clinical, pathologic, and molecular factors can be used to predict an increased likelihood of metastatic disease and death from prostate cancer. The most important of these are a short PSA doubling time after radical prostatectomy, a short interval to biochemical recurrence after radiation therapy, a higher Gleason score, and a local recurrence following local therapy. Where available, we use the results of PET scanning (PET-positive versus PET-negative status) as well as risk grouping based on PSA doubling time and Gleason score to stratify likely prognosis and need for treatment. (See 'Specific prognostic factors' 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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