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".)
The use of salvage radiation therapy for males who have a persistently elevated or rising PSA following radical prostatectomy for early stage disease will be reviewed here. Other topics relevant to patients with a rising PSA include:
●(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".)
GENERAL APPROACH — Following radical prostatectomy, the serum level of PSA should become undetectable since all normal prostate tissue, as well as the tumor, is removed. Thus, monitoring PSA after definitive treatment of localized prostate cancer leads to the identification of males with a PSA-only (biochemical) recurrence. For males in whom there is a significant likelihood that disease is confined to the prostatic bed, salvage therapy may result in prolonged disease-free survival (algorithm 1).
●For patients with a confirmed serum PSA ≥0.2 ng/mL following radical prostatectomy, careful evaluation is required to rule out the possibility of distant metastases. (See 'Definition of biochemical failure after radical prostatectomy' below and "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'Accuracy of individual tests and procedures'.)
●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 transrectal ultrasound imaging. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'Postprostatectomy recurrence'.)
●For patients without disseminated disease who are candidates for salvage therapy, salvage radiation therapy is the primary treatment option.
●For patients without disseminated disease who have undergone radical prostatectomy and are not candidates for salvage therapy, systemic therapy may be indicated. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer".)
DEFINITION OF BIOCHEMICAL FAILURE AFTER RADICAL PROSTATECTOMY — All prostate tissue should be removed during a successful radical prostatectomy. Postoperatively, a detectable and rising serum PSA using standard immunoassays is indicative of residual prostatic tissue, which presumably represents locoregional or systemic cancer [1]. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'After radical prostatectomy'.)
Guidelines — The most widely accepted criterion for patients who have undergone radical prostatectomy is that of the American Urological Association (AUA) [2]. 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.
Low, persistently elevated PSA — Although successful treatment of prostate cancer should remove the sources of PSA from both the cancer and the normal prostate, some patients will have a persistently elevated PSA after surgery, particularly when an ultrasensitive immunoassay is used.
A stable serum PSA <0.2 ng/mL could represent "retained normal prostate tissue" rather than persistent or recurrent disease, and the natural history of disease in these patients may not vary from that in those with an undetectable serum PSA following surgery. The optimal management of patients with a low detectable serum PSA that remains stable is controversial. Given the uncertainty about the meaning of these low levels of PSA, our approach is to monitor these patients without specific therapy.
The natural history of patients with a persistently elevated PSA is illustrated by two large series:
●A retrospective series of 566 males who had undergone radical prostatectomy found that 419 (74 percent) had an undetectable PSA (ie, ≤0.03 ng/mL) following surgery, 93 (16 percent) had a detectable PSA that remained stable but <0.2 ng/mL, and 54 (10 percent) had a detectable PSA that was unstable (two subsequent increases in serum PSA and/or a PSA velocity of ≥0.05 ng/year) [3]. The seven-year biochemical recurrence-free survival rates for these three groups were 95, 94, and 37 percent, respectively.
●Another retrospective series from two centers analyzed prostate-cancer-specific mortality in 496 males who had been treated with radical prostatectomy and lymph node dissection over a 20-year period [4]. All had a serum PSA between 0.1 and 2 ng/mL at six to eight weeks after surgery. Median follow-up was 110 months. The 10-year freedom from prostate-cancer-specific mortality rate was 88 percent.
NATURAL HISTORY OF BIOCHEMICAL FAILURE — The natural history of a PSA-only recurrence can be highly varied, reflecting heterogeneous tumor biology. Biochemical failure by itself does not necessarily predict death from prostate cancer [5]. (See "Rising serum PSA following local therapy for prostate cancer: Definition, natural history, and risk stratification", section on 'Natural history after biochemical failure'.)
Impact of more sensitive diagnostic imaging — Notably, the definition of a PSA only recurrence was derived in an era where radiographic restaging consisted of radionuclide bone scans and computed tomography (CT) scans. These definitions are evolving with the emergence of positron emission tomography (PET) scanning using more sensitive prostate-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) as a replacement for restaging bone scanning 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.
Nevertheless, the majority of data reported below on the efficacy of salvage radiation therapy represent males who were identified as having an isolated biochemical failure on the basis of conventional imaging alone, with some notable exceptions. (See 'Patients selected using prostate-specific PET radiotracers' below.)
SALVAGE RADIATION THERAPY — For males with a recurrence following radical prostatectomy, salvage external beam radiation therapy (RT) can provide long-term disease control if the recurrence is encompassed within the treatment field and if a sufficient radiation dose can be delivered to eradicate the residual/recurrent cancer. The success of salvage RT depends on the dose and treatment volume (ie, prostate bed with or without pelvis) in addition to the localization of all clonogenic cells to the treatment field.
The use of salvage RT in this setting is consistent with guidelines from the American Urological Association (AUA) and the American Society for Radiation Oncology (ASTRO) [6].
Prostate bed radiation therapy — For males who have a PSA-only recurrence following radical prostatectomy and who have an otherwise favorable life expectancy, we recommend salvage prostate bed RT.
Benefits — The initial retrospective studies of RT in patients with a biochemical relapse after radical prostatectomy relied on biochemical relapse-free survival (bRFS) rather than cancer-specific survival or the development of metastatic disease in an effort to define which patients were most likely to benefit from salvage RT [7-12].
Factors associated with an improved bRFS after salvage prostate bed RT included a positive surgical margin at prostatectomy, a low PSA level at recurrence, and a long recurrence-free interval following initial surgery. In contrast, a short (eg, <6 months) PSA doubling time, Gleason score ≥8, a history of lymph node or seminal vesicle involvement at original diagnosis, and persistent elevation of PSA following RT were all associated with poorer bRFS in those managed with salvage prostate bed RT.
Although these studies have been used to define patients who are more likely to benefit from salvage RT, these analyses were retrospective and did not include a control group that was managed with observation rather than active intervention. Thus, the factors identified in these studies may have been prognostic for the development of a biochemical relapse and not predictive of improved cancer-specific survival in response to treatment with salvage RT [13]. The available evidence suggest that biochemical failure is not a surrogate end point for overall survival in recurrent prostate cancer [14].
Three, large, retrospective, single-institution series provide conflicting data on whether or not salvage RT as a single modality can prolong survival:
●In a series of 2657 males treated at the Mayo Clinic who had a biochemical recurrence following radical prostatectomy, 856 (32 percent) received salvage RT [15]. On multivariate analysis, salvage RT significantly reduced the incidence of a subsequent local recurrence (hazard ratio [HR] 0.13, 95% CI 0.06-0.28). However, salvage RT did not significantly decrease mortality compared with those not receiving salvage RT following a biochemical recurrence (5- and 10-year survival rates 92 versus 91 and 70 versus 69 percent, respectively).
●On the other hand, a survival benefit for salvage RT was suggested in a study from Johns Hopkins that analyzed 635 patients who had either a biochemical or a local recurrence following radical prostatectomy [13]. At recurrence, patients were managed with observation, salvage prostate bed RT alone, or salvage RT in combination with hormonal therapy in 63, 25, and 12 percent of cases, respectively. Cancer-specific survival was significantly prolonged in patients who received RT, with or without hormonal therapy, compared with observation (96 and 96 versus 88 percent at five years, and 82 and 86 versus 62 percent at 10 years).
In this study, the benefit in survival was limited to those with a short PSA doubling time (<6 months) [13]. Although this group had a worse prognosis compared with those with a longer PSA doubling time, results suggest that not all of these patients have occult metastases and that significant benefit is still possible in those with a short PSA doubling time [5].
●RT also appeared to prolong survival in a cohort of 519 males who had a biochemical recurrence following radical prostatectomy at Duke between 1988 and 2008 [16]. Salvage RT (predominantly to the prostate bed) was given, either alone or as part of a combined approach that included androgen deprivation therapy (ADT), in 219 of these patients (37 percent). At a median follow-up of 11 years, multivariate analysis demonstrated a significant decrease in all-cause mortality both for those with a PSA doubling time <6 months and in those with a PSA doubling time ≥6 months (adjusted HR 0.53 and 0.52, respectively).
Patients selected using prostate-specific PET radiotracers — The development of more sensitive prostate specific radiotracers for positron emission tomography (PET) scanning has significantly altered the landscape of treatment for males with a rising PSA after definitive local therapy by more accurately defining disease extent. Where feasible, we incorporate PET scanning using sensitive prostate cancer specific radiotracers such as F-18 fluciclovine into radiotherapy decision making and planning.
All of the data described above on the benefits of salvage prostate bed RT were derived from studies that utilized conventional radiographic imaging for diagnostic evaluation of a postprostatectomy rising PSA. Emerging data support the view that outcomes may be improved with the inclusion of PET scanning using sensitive prostate cancer specific radiotracers into radiotherapy decision making and planning [17,18]. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'More sensitive prostate cancer-specific PET tracers'.)
As an example, in the EMPIRE-1 trial, 165 males with a detectable PSA postprostatectomy and negative conventional imaging (no extrapelvic or other bone findings) were randomly assigned to radiotherapy directed by conventional imaging alone or to conventional imaging plus F-18 fluciclovine PET scanning [17]. In the conventional imaging group, RT decisions were based on presurgical disease features, prostatectomy pathologic findings, and on PSA trajectory. RT to the prostate bed only or additionally to the pelvis, was delivered at the discretion of the treating clinician. In the F-18 fluciclovine group, RT decisions were rigidly determined by PET findings, which were categorized as extrapelvic or skeletal uptake (no RT), pelvic nodal uptake (RT to the pelvic and prostate bed), uptake in prostate bed only (RT to prostate bed), or no uptake (RT to the prostate bed only).
Serum PSA prior to RT was similar in both the conventional imaging (median 0.34, range 0 to 82) and F-18 fluciclovine groups (median 0.34, range 0 to 92). PET findings resulted in 4 of the 83 patients in the F-18 fluciclovine group having RT aborted, and these patients were not included in the survival analysis. In the modified intention to treat population, three-year event-free survival was significantly higher in the F-18 fluciclovine PET scanning group (63 versus 75.5 percent, difference 12.5 points, 95% CI 4.3-20.8, p = 0.0028). A difference in failure-free survival was also seen between the two groups at four years (51 versus 76 percent).
While these data are intriguing, the limiting factor, at least in the United States, is insurance coverage for F-18 fluciclovine PET in the setting of a very low but rising PSA level after prostatectomy.
Other prostate-specific radiotracers are available and approved for PET scanning in males with a rising PSA after initial definitive local therapy, including GA-68 PSMA-11, flotufolastat F-18, and F-18 DCFPyL (piflufolastat F-18), which also have greater sensitivity than conventional imaging for both nodal and distant metastases, even in males with a very low PSA level. Several studies have shown that the inclusion of one of these PET scans in the diagnostic imaging evaluation of a male with a rising PSA after prostatectomy alters management in 50 percent or more, with a greater sensitivity than F-18 fluciclovine at PSA levels <2 ng/mL. However, availability of these radionuclides is limited, and as with F-18 fluciclovine, insurance coverage may be a limiting factor. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'Ga-68 and F-18 PSMA PET/CT'.)
Timing — For males in whom a PSA recurrence has been documented and who are candidates for salvage therapy, salvage RT should be initiated promptly. Prompt initiation of salvage RT in appropriate candidates once a PSA relapse has been documented appears to be more effective when the serum PSA is lower (ie, <0.5 ng/mL) compared with salvage therapy once the serum PSA is >0.5 ng/mL. Although there are no randomized trials defining the optimal timing, multiple studies provide support for this approach [19-23]:
●The potential role of early salvage RT is illustrated by a multicenter cohort of 472 who experienced a biochemical relapse after radical prostatectomy and received salvage RT while their serum PSA was <0.5 ng/mL [20]. With a median follow-up of four years, the five-year bRFS was 73 percent. On multivariate analysis, factors associated with a better outcome following salvage RT included pathologic stage (T2 versus T3), negative versus positive surgical margins, Gleason 6 versus Gleason 7 or 8 disease, and lower pre-RT serum PSA. A nomogram is available to estimate the probability of a biochemical relapse after early salvage RT (figure 1) [20].
●In a retrospective analysis of 2460 patients treated at 10 tertiary care centers, the five-year freedom from biochemical failure for patients correlated with lower serum PSA prior to salvage RT (71, 63, 54, 43, and 37 percent for those with serum PSA 0.01 to 0.20, 0.21 to 0.50, 0.51 to 1.0, 1.01 to 2.0, and >2.0 ng/mL, respectively), as did the 10-year freedom from distant metastases (91, 85, 81, 80, and 63 percent, respectively) [23].
Information from the pre-salvage-RT PSA was combined with the surgical Gleason score, presence or absence of extraprostatic extension, status of surgical margins, presence or absence of seminal vesicle invasion, prostate bed RT dose, and use of neoadjuvant or concurrent ADT to generate a nomogram that can be used to predict the likelihood of 5- and 10-year freedom from biochemical failure (figure 2).
●In a study of 1106 patients treated over a 26-year period at the Mayo Clinic, patients with a serum PSA ≤0.5 ng/mL were compared with patients with a serum PSA >0.5 ng/mL [22]. There was a significantly lower incidence of biochemical relapse at 10 years (60 versus 68 percent), distant metastases (13 versus 25 percent), and cancer-specific mortality (6 versus 13 percent).
Dose of radiation — For most males, we suggest a minimum radiation dose of 66 Gy for salvage RT.
The evidence for the appropriate dose of radiation in the postoperative setting is much less robust than in the definitive setting. There are large retrospective series and two randomized trials that help to inform practice:
●A large meta-analysis of more than 10,000 patients from 71 retrospective series with median follow-up 52 months concluded that doses above 70 Gy were more efficacious [24].
●Another retrospective analysis of 1108 patients treated at 10 centers came to similar conclusions [25]. The cohort was limited to patients who had margin-positive disease at radical prostatectomy, had a serum PSA ≤2 ng/mL, and did not receive neoadjuvant or concurrent androgen suppression. For patients treated with <66 Gy, the 5- and 10-year rates of biochemical recurrence were 40.6 and 56.9 percent, respectively. In contrast, for those treated with 66 to 69.9 Gy, the 5- and 10-year rates of biochemical recurrence were 34.3 and 42.3 percent, respectively; for those treated with ≥70 Gy, the rates were 28.5 and 38.6 percent, respectively. On multivariate analysis, the differences for those treated with ≥66 Gy were significantly different from those treated with <66 Gy.
There are two published randomized trials evaluating radiation dose in the postoperative setting that are also relevant; neither showed an advantage for higher doses than 64 to 66 Gy [26-29]:
•The multicenter Swiss SAKK 09/10 trial compared 64 with 70 Gy in the salvage-RT setting in 350 males with a rising PSA after radical prostatectomy at least 12 weeks previously and no evidence of macroscopic disease. In an initial report [27], the higher dose was associated with slightly higher acute urinary symptoms and patient-reported quality of life, but a subsequent analysis revealed no difference in urinary incontinence according to dose [26].
At a median follow-up of 6.2 years, there was no difference in the six-year freedom from biochemical progression rate with higher-dose RT (61.3 versus 62.3 percent, HR for biochemical progression 1.14, 95% CI 0.82-1.60), and there were also no differences in clinical progression-free survival, time to hormonal treatment, or overall survival [30]. Higher-dose therapy was associated with significantly higher rates of late grade 2 or 3 gastrointestinal toxicity. The authors concluded that conventional dose salvage RT to the prostate bed is sufficient for individuals with early biochemical progression after RP.
•A Chinese randomized controlled trial compared 66 with 72 Gy in patients with a biochemical recurrence following prostatectomy [28]. One hundred and forty-four patients were enrolled. The primary endpoint was biochemical progression-free survival, and the median follow-up was 48 months. There was no difference in four-year biochemical progression-free survival between the 66 and 72 Gy cohorts (75.9 versus 82.6 percent; p = 0.299). An unplanned subgroup analysis did observe improved biochemical progression-free survival for the 72 Gy group with Gleason scores of 8 to 10. No differences in acute or late grade 2+ genitourinary or gastrointestinal toxicity were observed.
Neither of the randomized controlled trials were powered to show a survival difference.
Toxicity — Salvage RT after a previous radical prostatectomy is generally well tolerated, although there is frequently increased mild to moderate urinary bother and incontinence [26,31,32]. In a multi-institution database study of 959 males who received postoperative RT (81 percent as salvage and 19 percent as adjuvant therapy), the five-year rates of late grade 3 genitourinary and gastrointestinal side effects were 1 and 0.4 percent, respectively [31].
Salvage versus adjuvant radiation therapy — Careful surveillance and early salvage RT following surgery may be an appropriate alternative to immediate adjuvant RT for patients with high-risk primary prostate cancer managed with surgery. (See "Prostate cancer: Postoperative management of pathologic stage T3 disease, positive surgical margins, and lymph node involvement following radical prostatectomy", section on 'RT: adjuvant versus early salvage'.)
There currently are no randomized clinical trial results comparing these two approaches, although three phase III trials (RADICALS [NCT00541047], GETUG-17 [NCT00667069], and RAVES [NCT00860652]) are in progress. Data from retrospective series are discussed separately. (See "Prostate cancer: Postoperative management of pathologic stage T3 disease, positive surgical margins, and lymph node involvement following radical prostatectomy", section on 'RT: adjuvant versus early salvage'.)
Prostate bed RT plus androgen deprivation therapy — Largely based on results from the RTOG 9601 trial, for patients with a detectable PSA above 0.6 ng/mL after radical prostatectomy, we suggest adding short-term ADT in conjunction with radiation therapy (RT). We use ADT for two months before and during salvage RT (six months total). For individuals with a pre-RT PSA <0.6 ng/mL, there is no consensus on the value of ADT. The presence of high-risk features (Gleason >7, seminal vesicle involvement, and a PSA that never became undetectable) may provide support for use of ADT in such patients.
This recommendation is slightly different than updated guidelines from ASTRO/AUA, which recommend that clinicians offer ADT to males treated with salvage RT if the PSA is ≥0.2 ng/mL [6]. The decision to pursue hormone therapy should be made by the patient and a multidisciplinary team of providers using a shared decision-making model, taking into account the patient's history, values, preferences, quality of life, and functional status.
At least three contemporary randomized trials inform the decision to use ADT combined with salvage RT:
●In the phase III GETUG-AFU 16 trial, 743 males with a biochemical recurrence at least six months after radical prostatectomy (PSA >0.1 ng/mL) were randomly assigned to salvage prostate bed RT with a six-month course of ADT (goserelin) or to salvage RT alone [33]. At a median follow-up of 63 months, the addition of ADT significantly prolonged five-year progression-free survival compared with RT alone (80 versus 62 percent, HR 0.50, 95% CI 0.38-0.66), although five-year overall survival rates were not positively impacted (96 versus 95 percent, HR 0.7, 95% CI 0.4-1.2).
Benefits were maintained with longer follow-up. At a median follow-up of 112 months, 10-year rates of progression-free survival were also better in males who had received short-course ADT in conjunction with RT compared with RT alone (64 versus 49 percent, HR 0.54, 95% CI 0.43-0.68) [34]. No overall survival differences have been reported in this trial to date.
●The Radiation Therapy Oncology Group (RTOG) 9601 trial included 760 males with a detectable PSA (0.2 to 4.0 ng/mL) following radical prostatectomy and randomly assigned them to prostate bed RT plus placebo or to RT with antiandrogen therapy for 24 months (bicalutamide 150 mg/day) [35]. The median follow-up at the time of the report was 13 years. Overall survival at 12 years was significantly better with bicalutamide (76 versus 71 percent, HR 0.77, 95% CI 0.59-0.99), and this represented a reduction in 12-year prostate cancer mortality from 13.4 to 5.8 percent (p <0.001). An interaction was observed, however, with the treatment effect only observed in patients with a pretreatment PSA >1.5 ng/mL. Gynecomastia was more common in the bicalutamide group compared with the placebo group (70 versus 11 percent).
A later secondary analysis has further clarified the strong interaction between pre-RT PSA and treatment effect [36]. Investigators examined the effects of pre-RT PSA level to determine if PSA could be a predictive biomarker. The results indicate that the overall survival benefit of bicalutamide was observed in males with pre-RT PSA levels above 0.6 ng/mL. Additionally, in those receiving early salvage RT (PSA ≤0.6 ng/mL, n = 389), there was no improvement in overall survival (HR 1.16, 95% CI 0.79-1.70), an increased other-cause mortality hazard (subdistribution HR 1.94, 95% CI 1.17-3.20, p = 0.01), and an increased odds ratio of late grades 3 to 5 cardiac and neurologic toxic effects (odds ratio 3.57, 95% CI 1.09-15.97, p = 0.05). The findings suggest that pre-RT PSA is both a prognostic and predictive biomarker in that the PSA level can be used to tailor the use of ADT in the postoperative setting.
Interpretation of the trial is complicated since the patient population included both patients with a residual elevation of serum PSA following radical prostatectomy and those with a PSA that subsequently rose. Furthermore, the trial used a dose of bicalutamide of 150 mg/day, which is more than the approved dose in the United States and may account for the difference in the incidence of gynecomastia.
●Additional support for the benefits of adding short-term ADT to prostate bed RT is provided by the RTOG 0534 (SPPORT) trial, in which 1792 patients with a biochemical recurrence following radical prostatectomy were randomly assigned to prostate bed RT (PBRT) alone (64.8 to 70.2 Gy), PBRT plus ADT for four to six months starting two months prior to RT (luteinizing hormone-releasing hormone [LHRH] agonist plus flutamide or bicalutamide), or PBRT plus pelvic node RT (pelvic lymph node RT [PLNRT]) plus concurrent ADT [37]. The primary endpoint was freedom from progression (FFP), which was defined as an increase in PSA according to the Phoenix definition (nadir +2 ng/mL), clinical progression (local, regional, or distant), or death from any cause. In the final analysis (median follow-up 8.2 years), the addition of short-term ADT to PBRT significantly improved five-year FFP (81 versus 71 percent, adjusted HR 0.60, 95% CI 0.47-0.77), but this did not translate into a significant difference in risk for distant metastases (6.1 versus 8.5 percent, HR 0.74, 95% CI 0.49-1.11) or prostate cancer specific death (0.9 versus 2.9 percent, HR for survival 0.73, 95% CI 0.42-1.28). The mean levels of preradiotherapy baseline PSA were similar in both groups (0.47 [range 0.1-1.96] versus 0.51 ng/mL [range 0.1 to 1.93] for the groups undergoing PBRT without and with ADT, respectively).
The impact of adding ADT to PLNRT are described in detail below. (See 'Prostate bed plus pelvic lymph node radiation therapy' below.)
More recently, trials are testing the value of adding a short course of treatment with an androgen receptor pathway inhibitor such as enzalutamide to salvage RT [38]. However, whether this strategy is more effective or less toxic than RT plus short-course ADT will require a randomized trial directly comparing both approaches.
Impact of molecular testing — 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 1). Several of these, including the Decipher Genomic Classifier (GC) have shown some utility for prognostication following radical prostatectomy, and in some cases, informed treatment of males with biochemically recurrent disease after radical prostatectomy.
In an ancillary study of the RTOG 9601 trial of salvage RT plus bicalutamide versus placebo, described above, GC scores were generated from 486 of the 760 randomized patients, and 352 that passed microarray quality control comprised the final cohort for analysis [39]. 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 and prostate cancer specific mortality. Although the planned original analysis was not powered to detect a significant treatment interaction by GC score, the estimated absolute effect of bicalutamide on 12-year overall survival was less when comparing patients with a lower versus a higher GC score (2.4 versus 8.9 percent), which was especially prominent when the analysis was limited to males receiving early salvage RT at a PSA level <0.7 ng/mL in whom the use of bicalutamide for males with a lower GC values associated with a lower overall survival as compared with those with higher values (-7.8 versus +4.6 percent).
Prospective validation is recommended before generalized use of GC score for treatment decision making on the omission of ADT can be endorsed. This should preferably take place in a trial in which males with a high GC are randomly assigned to RT alone or with ADT.
The clinical utility of molecular prognostic tests for prostate cancer is addressed in detail elsewhere. (See "Molecular prognostic tests for prostate cancer".)
Prostate bed plus pelvic lymph node radiation therapy — Whether RT should be limited to the prostate bed or should include pelvic irradiation is controversial. For most males, we consider the standard of care to be prostate bed RT plus short-term ADT. Given the results of the RTOG 0534 trial, we discuss the option of adding pelvic nodal RT to prostate bed RT and short-term ADT with patients for shared decision making, with full disclosure of the uncertainty of benefits and potential harms. Patients who place a high value on optimizing prostate cancer outcomes and a relatively lower value on avoiding treatment-related toxicity might reasonably choose extended lymph node irradiation, despite the uncertainty of long-term benefit.
The available data on prostate bed plus pelvic node RT versus prostate bed RT alone are as follows:
●The role of more extensive pelvic irradiation has been addressed in two trials in males whose localized prostate cancer was managed with definitive RT. In that setting, both trials (RTOG 9413 and GETUG-01) failed to show an improvement in survival among males who were assigned to treatment with prostate plus pelvic lymph node RT compared with those assigned to treatment limited to the prostate [40,41]. However, these trials used RT for primary therapy of prostate cancer rather than in the salvage setting. These trials, as well as other data addressing the extent of the RT field, are discussed separately. (See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement", section on 'Whole-pelvis versus prostate-only radiation therapy'.)
●However, additional information is available from the phase III RTOG 0534 trial, which directly tested the benefit of including both the prostate bed and the pelvic lymph nodes in the radiation field (PLNRT) with concurrent short-term ADT versus prostate bed RT (PBRT) alone or with short-term ADT in patients with a PSA-only recurrence after radical prostatectomy [37]. The benefits of adding ADT to PBRT are discussed above. (See 'Prostate bed RT plus androgen deprivation therapy' above.)
In the final analysis (median follow-up 8.2 years), compared with PBRT alone, PLNRT plus ADT was associated with a significantly better five-year FFP (87 versus 71 percent, HR 0.50, 95% CI 0.39-0.64), a lower risk of distant metastases (4.5 versus 8.5 percent, HR 0.52, 95% CI 0.34-0.81) and fewer prostate cancer specific deaths (0.7 versus 2.9 percent, HR 0.51, 95% CI 0.27-0.94). However, when compared with PBRT plus ADT, there was only a trend toward benefit of PLNRT that was not statistically significant for five-year freedom from progression (87.4 versus 81.3 percent, HR 0.82, 95% CI 0.63-1.07), risk of distant metastases (4.5 versus 6.1 percent, HR 0.71, 95% CI 0.45-1.12) or prostate cancer-specific death (0.7 versus 0.9 percent, HR 0.70, 95% CI 0.37-1.32).
From a toxicity standpoint, acute ≥grade 2 toxicity was more common in those undergoing PLNRT compared with PBRT plus ADT (44 versus 36 percent, respectively). When compared with PBRT plus ADT, treatment-related ≥grade 2 acute gastrointestinal toxicity (predominantly diarrhea) was slightly higher with PLNRT (7 versus 4 percent). However, this was based on relatively few events in either group. There was also more acute ≥grade 2 bone marrow toxicities with PLNRT (5 versus 2 percent), but this was related mostly to treatment-associated lymphopenia. There were no other significant toxicity differences between the groups.
Given the lack of significant benefit for adding pelvic nodal RT to prostate bed RT plus short-term ADT, in our view, the option of adding pelvic nodal RT to prostate bed RT and short-term ADT cannot be considered a standard approach.
Subsequent biochemical recurrence — Serum PSA levels should be monitored after salvage RT for a biochemical recurrence following radical prostatectomy. Evidence of a further biochemical recurrence is not uncommon in this situation.
The primary approach to management of a subsequent biochemical recurrence is ADT. The optimal timing for initiation of ADT in this situation is not clear. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'ADT monotherapy'.)
SYSTEMIC THERAPY — For patients with rising PSA after radical prostatectomy, if salvage radiation is not appropriate, risk stratification is appropriate to determine which patients can be monitored and which ones should receive systemic therapy. This is discussed in detail elsewhere.(See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'High-risk features' and "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'Low-risk features'.)
ROLE OF SURGERY FOR AN ISOLATED PELVIC RECURRENCE — We do not generally refer males with an isolated pelvic recurrence for salvage surgery. For patients in whom salvage radiation therapy is not appropriate and who have a rising PSA following radical prostatectomy, the standard approach is systemic therapy (ie, androgen deprivation therapy [ADT]).
In rare cases, an isolated recurrence may be detected in pelvic lymph nodes using more sensitive imaging techniques, such as prostate-specific membrane antigen (PSMA), fluciclovine, or carbon-11 (11C)-choline positron emission tomography (PET)/computed tomography (CT). If detailed evaluation (including negative biopsies of the prostatic fossa) does not reveal other sites of metastatic disease, salvage lymph node dissection may be considered and may result in a delay in the initiation of prolonged ADT [42]. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'More sensitive prostate cancer-specific PET tracers'.)
In a retrospective, single-institution experience of 59 patients treated this way over a six-year period, 35 (59 percent) achieved a complete biochemical response [43]. With a minimum follow-up of five years, the five- and eight-year biochemical relapse-free survival rates were 29 and 22 percent, respectively, but at eight years, cancer-related mortality rates were only 19 percent. Additional observational series have yielded similar results [44-46]. However, others note poor long-term prostate cancer-specific survival with salvage lymph node dissection alone for presumed isolated nodal recurrence postprostatectomy even when more sensitive imaging techniques are used, arguing for the early administration of ADT given the high risk of systemic disease dissemination [47].
OLIGOMETASTATIC DISEASE — The presence of a rising PSA may lead to the identification of oligometastatic disease at a remote site or that is limited to the pelvic nodes. With the increasing use of more sensitive imaging techniques that utilize prostate-specific radiotracers, this is an increasing subset of patients with a rising PSA post-local treatment. (See 'Impact of more sensitive diagnostic imaging' above and "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation", section on 'More sensitive prostate cancer-specific PET tracers'.)
Management of these males (initial systemic therapy and the contribution of focal radiotherapy for oligometastatic disease) is discussed in detail elsewhere. (See "Initial systemic therapy for advanced, recurrent, and metastatic noncastrate (castration-sensitive) prostate cancer" and "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer", section on 'Metastasis-directed therapy for oligometastatic disease'.)
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
●The routine monitoring of prostate-specific antigen (PSA) after treatment of early stage prostate cancer has led to the identification of males with a PSA-only (biochemical) recurrence. In this situation, increases in serum PSA over the pretreatment baseline are not accompanied by symptoms or signs of progressive disease. 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. (See 'Guidelines' above.)
●For patients who have a PSA-only recurrence following radical prostatectomy and who have an otherwise favorable life expectancy, we recommend salvage prostate bed radiation therapy (RT) (algorithm 1) (Grade 1B).
●The development of more sensitive prostate specific radiotracers for positron emission tomography (PET) scanning has significantly altered the landscape of treatment for males with a rising PSA after definitive local therapy by more accurately defining disease extent. This can improve outcomes from salvage radiotherapy. Where feasible, we incorporate PET scanning using sensitive prostate cancer specific radiotracers such as F-18 fluciclovine into radiotherapy decision making and planning. (See 'Patients selected using prostate-specific PET radiotracers' above.)
●For patients receiving salvage RT, we suggest a minimum RT dose of at least 66 Gy (Grade 2C). (See 'Dose of radiation' above.)
●For patients with a pre-RT PSA of ≥0.6 ng/mL, we suggest adding short-term androgen deprivation therapy (ADT) in conjunction with RT (Grade 2B). We use ADT for two months before and during salvage RT (six months total). (See 'Prostate bed RT plus androgen deprivation therapy' above.)
For patients with a pre-RT PSA <0.6 ng/mL, there is no consensus on the value of ADT. The presence of high-risk features (Gleason >7, seminal vesicle involvement, and a PSA that never became undetectable) can be used to provide support for ADT in patients with a pre-RT PSA <0.6 ng/mL.
●The optimal treatment volume is controversial. For most males, we consider the standard of care to be prostate bed RT only plus short-term ADT. However, given the results of the Radiation Therapy Oncology Group (RTOG) 0534 trial, we discuss the option of adding pelvic nodal RT to prostate bed RT and short-term ADT with patients for shared decision making, with full disclosure of the uncertainty of benefits and potential harms. Patients who place a high value on optimizing prostate cancer outcomes and a relatively lower value on avoiding treatment-related toxicity might reasonably choose extended lymph node irradiation, despite the uncertainty of long-term benefit. (See 'Prostate bed plus pelvic lymph node radiation therapy' above.)
●The management of males with a low but persistently elevated PSA (ie, <0.2 ng/mL) using ultrasensitive immunoassays is controversial. Many of these cases represent retained normal prostate tissue; however, those with progressive increases in serum PSA may be at increased risk for a subsequent biochemical recurrence. We suggest monitoring these patients without specific therapy (Grade 2C). (See 'Low, persistently elevated PSA' above.)
●For males who have a rising PSA following radical prostatectomy in whom salvage RT is not appropriate, the standard approach is systemic therapy alone. (See 'Systemic therapy' above.)
For older adult males and those with severe comorbidities, observation in the absence of overt metastases is a reasonable alternative. (See 'Natural history of biochemical failure' 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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