Prostate cancer: Postoperative management of pathologic stage T3 disease, positive surgical margins, and lymph node involvement following radical prostatectomy

INTRODUCTION — Prostate cancer is increasingly diagnosed in younger men and at an earlier disease stage, when the tumor is confined to the prostate. Men who are managed with radical prostatectomy are staged pathologically based on pathologic examination of the resection specimen; some will have histopathologic extension beyond the prostate (pT3), positive margins upon examination of the surgical specimen (R1), or lymph node involvement (table 1 and table 2).

The management of patients with pT3/T4 disease, positive surgical margins, or pathologic lymph node involvement following radical prostatectomy for clinically localized disease will be reviewed here.

The management of patients with clinical lymph node involvement identified during pretreatment staging is discussed elsewhere. (See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement", section on 'Clinical evidence of lymph node involvement'.)

PATHOLOGIC VERSUS CLINICAL STAGING — The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) system is used to stage newly diagnosed prostate cancer (table 1 and table 2). This system incorporates the anatomic extent of disease, including the primary tumor (T), regional lymph nodes (N), distant metastases (M), and margin status (R). In addition, the baseline serum prostate-specific antigen (PSA) and histologic grade group (table 3) (based on the Gleason score) are incorporated to divide patients into prognostic stage groupings (table 4) [1]. Imaging findings are not incorporated into pathologic staging. (See "Initial staging and evaluation of males with newly diagnosed prostate cancer", section on 'Clinical versus pathologic TNM staging'.)

The pretreatment evaluation provides the information for the clinical (c) stage, which forms the basis for the initial treatment decisions, along with patient age, overall medical condition, and the presence or absence of symptoms. For patients whose initial treatment includes radical prostatectomy, additional information is obtained from histopathologic examination of the prostatectomy specimen, and this forms the basis for the pathologic (p) stage.

Clinical staging may underestimate or overestimate the anatomic extent of disease. Patients with cT1N0 or cT2N0 disease may be reclassified as pT3 or N1 based on these results. Conversely, patients thought to have more extensive (cT3) disease may be reclassified as pT2. If surgical margins are positive for tumor (residual microscopic disease), staging is modified by an "R1" descriptor, while negative margins are designated "R0."

pT3 involvement is defined by the presence of extraprostatic disease. pT3 stage is subdivided into pT3a, which includes extraprostatic extension (sometimes also called "extracapsular" extension) or microscopic invasion of the bladder neck, and pT3b, which includes seminal vesicle invasion. Invasion into the rectum, levator muscles, and/or pelvic wall is defined as pT4 disease.

PATHOLOGIC T3 OR MARGIN-POSITIVE DISEASE

Risk of recurrence — In contemporary series, between 50 and 75 percent of men with pathologic (p) T3 disease will ultimately have a biochemical relapse following radical prostatectomy (defined as a detectable serum prostate-specific antigen [PSA; >0.2 ng/mL]) [2-4].

T3a versus T3b disease — The pattern of disease recurrence appears to differ for men with pT3a disease compared with those with pT3b disease [5]. With extraprostatic extension (pT3a), local control tends to be more of a problem, particularly in the presence of positive margins. By contrast, men with seminal vesicle invasion (pT3b) are at higher risk for distant disease recurrence, regardless of the status of the surgical margins. The effectiveness of adjuvant radiation therapy (RT) does not appear to differ in men with pT3a disease as compared with those with pT3b disease. (See 'RT: adjuvant versus early salvage' below.)

Positive margins — The natural history of men with positive resection margins (R1) after radical prostatectomy is variable. Even when multiple positive margins are present, not all men recur [6-10].

The variable natural history is illustrated by a contemporary multicenter analysis in which positive surgical margins were identified in 2607 of 11,521 men (23 percent) who had undergone radical prostatectomy [11]. The 15-year cancer recurrence rate was significantly increased compared with that in those with negative margins (10 versus 6 percent), although the median follow-up was only 56 months. Furthermore, in a multivariable analysis that incorporated Gleason score, seminal vesicle invasion, and the use of postoperative RT, the impact of positive surgical margins was not statistically significant. An understanding of the impact of positive surgical margins and adjuvant therapy requires recognition of factors that are modifiable and those that are not. Non-modifiable risk factors are largely due to the inherent biology of the disease and will drive both recurrence rates and the impact adjuvant therapy has on the course of the disease.

Multiple factors have been identified that influence the risk of recurrence when a positive margin is identified in the surgical specimen:

●The risk classification of the patient at presentation influences the likelihood of recurrence in those with a positive surgical margin. In a single-institution series of 1268 patients, 21 percent of cases had positive surgical margins [6].

●The number and location of positive margins influence the risk of recurrence. In a series of 1667 evaluable men who underwent radical prostatectomy, 1295 had negative margins, 96 had a solitary positive apical margin, 82 had a solitary positive nonapical margin, and 194 had multiple positive margins (78, 6, 5, and 12 percent, respectively) [12]. Among those with a solitary positive apical margin, a solitary positive nonapical margin, and multiple positive margins, the three-year rates of biochemical recurrence were 13, 18.6, and 27 percent, respectively. However, late relapses may be seen for many years after radical prostatectomy.

●The primary Gleason score at the positive surgical margin also influences the likelihood of systemic progression and cancer-specific survival. In a series of 1036 patients who had undergone radical prostatectomy, 338 (33 percent) had positive margins [13]. At a median follow-up of 13 years, primary Gleason grade 4 at the resection margin was associated with worse systemic disease-free survival compared with primary Gleason grade 3 or negative surgical margins (74 versus 90 versus 93 percent, respectively). Similarly, cancer-specific survival was worse in this group (86 versus 96 versus 97 percent, respectively).

Management — The following represents our approach to these patients:

●For men with pT3 disease, negative nodes, negative or minimally positive surgical margins following radical prostatectomy, and an undetectable serum PSA, we suggest early salvage RT at the first sign of PSA recurrence rather than adjuvant RT. Delayed RT avoids radiation complications in those who will never require additional treatment, particularly since adjuvant RT appears to adversely affect urinary continence. (See 'RT: adjuvant versus early salvage' below.)

●In occasional circumstances, men with higher-risk disease (eg, extensively positive surgical margins, especially with grade group 4 or 5 disease (table 3)) may consider adjuvant external beam RT following radical prostatectomy, rather than salvage RT at the first sign of a biochemical recurrence. However, careful monitoring for evidence of a biochemical recurrence, followed by salvage RT at the earliest evidence of relapse, is an acceptable alternative. (See 'RT: adjuvant versus early salvage' below.)

●Androgen deprivation therapy (ADT) is not routinely recommended in the adjuvant setting for patients who have node negative disease. For most men, early salvage RT is preferred over adjuvant RT. ADT given in conjunction with early salvage RT for node negative patients may be considered if the PSA level at time of salvage is elevated, particularly >0.7 ng/mL and considering the results of RTOG 9601, GETUG 16, and a preliminary report of RTOG 0534. Concomitant ADT with salvage RT may also be considered with gross residual recurrence in the prostate bed, a rapid PSA doubling time, or other high risk features. We do not routinely recommend using ADT in conjunction with adjuvant RT or early salvage RT following prostatectomy. However, this approach can be considered in men with multiple features of high-risk disease (eg, grade group 4 or 5 disease (table 3), positive seminal vesicles, and/or positive margins). (See 'Concurrent ADT' below.)

●The role of adjuvant ADT alone after prostatectomy is uncertain. We reserve this approach (typically high-dose bicalutamide [150 mg daily]) as an alternative to adjuvant RT for a very select population of sexually active young men who have preserved erectile function after radical prostatectomy for high-risk, completely resected disease (eg, grade group 4 or 5 (table 3), pT3b), who are aware of the risk of gynecomastia, and who wish to avoid RT. (See 'ADT alone without radiation therapy' below.)

●There is no evidence that any form of chemotherapy (docetaxel, mitoxantrone) is beneficial in the adjuvant setting, and we recommend against this practice. (See 'Role of chemotherapy' below.)

●Patients with detectable postoperative PSA, particularly that above 0.2 ng/mL, are candidates for salvage RT and may also be candidates for additional staging workup, including advanced positron emission tomography (PET) agents, depending on PSA level. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation" and "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management".)

RT: adjuvant versus early salvage — For most men with pT3 or margin-positive, node-negative prostate cancer and an undetectable serum PSA following radical prostatectomy, we suggest salvage RT rather than adjuvant RT. However, given the risk of an early rapid recurrence, the option of adjuvant RT should be discussed with men who have extensive grossly positive surgical margins, especially in conjunction with grade group 4 or 5 disease (table 3). Careful monitoring for evidence of a biochemical recurrence, followed by salvage RT at the earliest evidence of relapse, is also an acceptable alternative.

●Adjuvant RT versus observation – Adjuvant RT decreases the risk of a biochemical relapse in select patients. It may also improve overall and metastasis-free survival in these select patients. However, the role of adjuvant RT, particularly compared with early salvage RT at the time of a biochemical relapse, is in evolution. Previous prospective randomized trials showing that adjuvant RT was associated with a reduced risk of recurrence in men at risk (ie, positive surgical margins, pathologic stage T3 disease, grade group 4 or 5 disease) were confounded by the use of salvage treatment (typically ADT) only at the time of clinical progression, and few men receiving adjuvant RT at all. More recent trials have favored early salvage RT rather than adjuvant RT for most men because of lower risks for overtreatment and fewer adverse events.

Arguments for adjuvant RT include the following:

•Extended follow-up from large clinical trials provides evidence that adjuvant RT is well tolerated and that it improves biochemical and local control rates in men who are found to have pT3 disease or diffusely positive resection margins at radical prostatectomy.

•There is also increasing evidence that postoperative RT improves metastasis-free and overall survival [14-17].

•Postoperative surveillance without treatment, followed by salvage RT at the first evidence of a rising serum PSA, entails the risk that distant metastases might develop in some men who might have been rendered disease free with immediate adjuvant RT.

Arguments against adjuvant RT include the following:

•Recommending adjuvant RT for all men with high-risk disease after prostatectomy means that RT will be administered to many men who may never require such treatment (ie, overtreatment).

•Adverse effects are more common with adjuvant RT. Consistent with quality of life (QOL) data from the prospective randomized SWOG trial 8794 [14], there are retrospective reports that suggest that men who receive adjuvant RT following radical prostatectomy have a lower rate of postprostatectomy recovery of urinary continence [18].

•At least three randomized trials and a meta-analysis of all three trials directly comparing adjuvant versus early salvage RT at the time of PSA progression support the view that prostate cancer-specific outcomes are similar with salvage as compared with adjuvant RT, but that the risk of overtreatment and its attendant treatment-related adverse effects are less with salvage therapy.

Postoperative RT in men with pT3 or margin-positive disease has been compared with observation in several randomized trials [14,15,19-21] and a meta-analysis [16]. The meta-analysis of EORTC 22911 [15], SWOG 8794 [19], and a third trial, ARO 96-02/AUO AP 09/95 [20], came to the following conclusions [16]:

•Compared with a wait-and-see strategy for pT3 or margin-positive prostate cancer, adjuvant RT significantly improved 10-year metastasis-free survival (odds ratio 0.77, 95% CI 0.62-0.96), biochemical progression-free survival (hazard ratio [HR] 0.48, p <0.00001), clinical progression-free survival, hormone-free survival, and local recurrence-free survival. However, none of these benefits translated into a significant improvement in either overall survival (HR 0.97, 95% CI 0.67-1.42) or prostate cancer-specific survival (HR 0.78, 95% CI 0.46-1.33).

•Grade 2 or higher genitourinary and gastrointestinal toxicities were significantly higher in the adjuvant therapy group, including urinary stricture (11 versus 5.7 percent) and urinary incontinence (6.9 versus 2.7 percent).

In our view, the trials included in this analysis used outdated treatments, and most men in the observation arms never received adjuvant RT, because further treatment was not typically administered until clinical progression, and most went straight to ADT. Furthermore, these trials included a heterogeneous group of patients with variable amounts of disease involvement, variable postoperative PSA levels, and varying or unspecified thresholds for the initiation of salvage RT. In current practice salvage RT is often initiated at the first sign of biochemical relapse (PSA >0.10-0.2 ng/mL). Thus, these trials, while demonstrating the benefit of adjuvant RT, did not adequately address the important question of whether early salvage therapy is as effective as immediate adjuvant therapy.

●Versus early salvage RT –Retrospective studies have given conflicting results regarding the relative merits of adjuvant versus early salvage RT [17,22,23]. Three randomized trials directly compared both approaches, and while they enrolled slightly different patient populations, and some used ADT while others did not, they have come to similar conclusions. Prostate cancer-specific outcomes are similar with salvage as compared with adjuvant RT, but the risk of overtreatment and its attendant treatment related adverse effects are less with salvage therapy [24-26]; a similar conclusion was reached in a meta-analysis of all three trials [27].

•The phase III RADICALS-RT trial randomly assigned 1396 men after surgery for high-risk prostate cancer (with either pT3-4, Gleason score 7 to 10 disease, preoperative PSA >10 ng/mL, or positive postoperative margins) to postoperative RT or delayed RT at the time of disease recurrence [24]. The use of ADT for up to two years was permitted at the discretion of the clinician, or if the patient was participating in a substudy of no ADT, six months of ADT, or two years of ADT. Within eight years after randomization, only 33 percent of the men in the salvage RT group had received RT. At a median follow-up of 4.9 years, five-year biochemical progression-free survival was not significantly better with immediate RT (85 versus 88 percent, HR 1.10, 95% CI 0.81-1.49), and the number of men who were free from nonprotocol ADT was similar (93 versus 92 percent). However, self-reported urinary incontinence was worse at one year with early RT, and grade 3 or 4 urethral strictures were more common with adjuvant RT as well (6 versus 4 percent). However, longer follow-up is required to assess the impact of adjuvant versus early salvage RT on the primary outcome measure of this trial (freedom from distant metastases at 10 years) and on survival.

•The RAVES trial was a multicenter Australian/New Zealand noninferiority randomized trial designed to directly compare adjuvant with early salvage RT in men with positive margins and/or pT3 disease; it was initially planned to accrue 470 patients but was closed prematurely because of unexpectedly low event rates after 333 patients had been randomly assigned [25]. ADT was not allowed. The primary endpoint was freedom from biochemical progression, with salvage RT deemed noninferior to adjuvant RT if freedom from biochemical progression at five years was within 10 percent of that for adjuvant RT. At a median follow-up of 6.1 years, one-half of the men randomized to salvage RT had RT triggered because of a PSA rise to ≥0.20 ng/ml, and there were only 17 patients with biochemical progression in either group. The five-year freedom from biochemical relapse was 86 percent with adjuvant RT versus 87 percent with salvage RT (HR 1.12, 95% CI 0.65-1.90). Rates of grade 2 or worse genitourinary toxicity were lower with salvage RT (54 versus 70 percent). Although salvage RT did not meet the trial-specified criteria for noninferiority, the authors concluded that salvage RT resulted in similar biochemical control as adjuvant RT, spared approximately 50 percent of men from pelvic radiation, and was associated with significantly less genitourinary toxicity.

•In the multicenter French randomized GETUG-AFU17 trial, randomly assigned men with pT3 or T4 prostate cancer with positive surgical margins were randomized to immediate versus delayed RT; all men received six months of triptorelin [26]. The trial was initially planned to enroll 718 men, but was closed prematurely after 424 patients were enrolled because of unexpectedly low event rates. At a median follow-up of approximately 75 months, 54 percent of the men undergoing salvage RT had initiated RT after biochemical relapse. Five-year event-free survival (the primary endpoint, defined as locoregional or distant disease relapse, biochemical progression, or death) was 92 percent in the adjuvant RT group, compared with 90 percent with salvage RT. More than twice as many men in the adjuvant RT group reported grade 2 or higher late genitourinary events (59 versus 22 percent), and rates of late erectile dysfunction were 28 versus 8 percent. As with the other two trials, the authors concluded that despite the lack of statistical power, that there was no evidence of event free-survival benefit for adjuvant as compared with early salvage RT, and that a policy of early salvage RT would spare men from overtreatment, and the associated adverse events.

•Preplanned meta-analysis was undertaken of all three trials (totaling 2153 men, of whom 1074 were randomly assigned to adjuvant RT and 1077 to early salvage RT); median follow-up ranged from 60 to 78 months [27]. Overall, 421 of the men randomized to early salvage RT had started salvage treatment (39 percent) at the time of the analysis. Event-free survival was defined by PSA rise to ≥0.4 ng/mL and rising after completion of any postoperative RT, clinical or radiologic progression, initiation of nontrial treatment, death from prostate cancer, or a PSA level ≥2 ng/mL at any time after randomization. The vast majority of first events were biochemical failures. Based on 270 total events in all men, there was no evidence that adjuvant RT improved event-free survival compared with early salvage RT (HR 0.95, 95% CI 0.75-1.21). This translates to a potential absolute difference of only 1 percent at five years in favor of salvage RT (95% CI -2 to 3 percent).

There was no good evidence that the effect on event-free survival varied according to predefined risk subgroups, including Gleason score, seminal vesicle involvement, or surgical margins. However, the fact that only 39 percent of men assigned to salvage RT had received it with median follow-up duration of five years or longer is consistent with a high population of patients with favorable-risk disease in all three studies, and limits the power of the high-risk subgroup analysis in this study. Furthermore, there was a disparity in the time frame for assessment for postradiotherapy PSA progression in the adjuvant and salvage RT groups that could have biased the result in favor of salvage RT for men with high-risk features at risk for early rapid PSA progression [28].

Men with high-risk disease — The positive, but relatively small, SWOG adjuvant therapy trial was conducted in the 1980s when, potentially, the pathology reports were not as refined as are contemporary reports. We suspect that, in that setting, adjuvant RT was mostly given for clinically very high-risk disease (eg, extensive positive margins, especially in the setting of high Gleason grade disease). Men with high-risk features such as these can have a rapid rise in PSA, and given the delay associated with delivery of salvage RT relative to adjuvant RT, disease within the RT treatment volume (ie, prostatic bed) may spread outside the RT treatment volume during that time [28]. The SWOG trial supports a potential survival advantage for such patients.

A benefit for adjuvant RT for men with high-risk disease was subsequently shown in the SWOG trial 8794, in which 425 men with pT3 or margin-positive prostate cancer were randomly assigned to immediate RT (60 to 64 Gy) or observation [14,19]. At a median follow-up of 12.6 years, adjuvant RT significantly improved both metastasis-free and overall survival compared with observation (median 14.7 versus 12.9 years, HR 0.71, 95% CI 0.54-0.94, and median 15.2 versus 13.3 years, HR 0.72, 95% CI 0.55-0.96) [19].

Subset analyses found that the benefits in metastasis-free and overall survival were independent of the Gleason score and included men with either detectable or undetectable postprostatectomy PSA levels and those with positive margins or seminal vesicle involvement. Adverse effects were more common in men receiving adjuvant RT [14]. These included rectal complications (3.3 versus 0 percent without adjuvant RT), urethral strictures (17.8 versus 9.5 percent), and total urinary incontinence (6.5 versus 2.8 percent).

A benefit for adjuvant rather than early salvage RT for men with high-risk disease was also suggested in a multi-institutional analysis of 26,118 men with pT2-3N0 or N1M0 prostate cancer who were consecutively treated with radical prostatectomy and pelvic lymphadenectomy at one of four medical centers in the United States and Germany [17]. Among the 2424 with adverse pathologic features (pN1, grade group 4 or 5, pT3/4 disease), 428 underwent adjuvant RT, 1031 had early salvage RT, and 965 received no RT; among the 23,694 men without adverse pathology, the corresponding numbers were 391, 3570, and 19,733 for adjuvant, salvage, and no RT, respectively. In an analysis adjusted for treatment propensity score (which represents the probability of treatment assignment conditional on observed baseline prognostic covariates), age at prostatectomy, treatment institution, and time dependent use of postprostatectomy androgen deprivation therapy (ADT), and after excluding men with a persistently positive PSA level, adjuvant RT significantly reduced all-cause mortality compared with early salvage RT in men with adverse pathologic features, including those with pN1 disease (10-year all-cause mortality 14 versus 22 percent, relative risk [RR] 0.66, 95% CI 0.44-0.99) or without pN1 disease (10-year all-cause mortality 5 versus 22 percent, RR 0.33, 95% CI 0.13-0.85). By contrast, there were no significant differences in all-cause mortality with adjuvant RT among men without adverse pathology (10-year all-cause mortality 8 versus 9 percent).

In our view, these data are insufficient to change our practice, which limits early adjuvant RT to those with grossly positive surgical margins, especially in conjunction with grade group 4 or 5 disease.

Influence of tissue-based molecular markers — No genetic test of the resected prostate can accurately aid in the selection of postsurgical RT (either adjuvant or salvage RT), and routine use of genomic markers in the postprostatectomy setting should not be offered. Routine monitoring of serum PSA postsurgery, and treatment with salvage RT prior to PSA ≥1 ng/mL is the standard of care in this setting.

Prognostic tests based on molecular and biomarker analysis of tumor tissue are emerging, specifically with an aim to better risk stratify both untreated and treated men with localized prostate cancer. One of these tests (Decipher Genomic Classifier with PORTOS score) has been developed and validated [29] to inform decisions about the value of adjuvant RT when the PSA is undetectable after radical prostatectomy. (See "Molecular prognostic tests for prostate cancer", section on 'Genomic classifier (Decipher)'.)

Year 2020 guidelines from the American Society of Clinical Oncology (ASCO) on the use of molecular biomarkers in localized prostate cancer lend moderate support to the use of the Decipher genomic classifier in situations where the assay result, when considered as a whole with routine clinical factors, is likely to affect management [30]. This may be in situations in which a Decipher score associated with a high risk of disease progression, for instance, helps to inform patient counseling in making a decision to proceed with adjuvant RT (eg, in a man with adverse pathologic features such as Grade Group 3 to 5 (table 3), T3a, node-positive, or margin-positive cancers, with an undetectable PSA). The panel, however, emphasized that in the absence of prospective clinical trial data, routine use of genomic markers in the postprostatectomy setting to select adjuvant treatment should not be offered. We agree with this position.

Notably, consensus-based guidelines from the National Comprehensive Cancer Network suggest that tumor-based molecular assays can be used to prognosticate risk of metastasis and prostate cancer-specific mortality in men with adverse features after prostatectomy, but they do not advocate their use for selecting men for adjuvant versus salvage RT [31].

Year 2018 guidelines for treatment of clinically localized prostate cancer from the combined American Urological Association (AUA), American Society for Radiation Oncology (ASTRO), and Society for Urologic Oncology (SUO) do not address the utility of molecular markers in this setting [32].

Concurrent ADT — The potential use and duration of ADT in conjunction with adjuvant or early salvage RT following prostatectomy remains controversial, and continues to evolve as more clinical trial data and observational studies become available. Outside the context of a clinical trial, we do not administer ADT to men undergoing adjuvant RT. Specific recommendations for concurrent ADT in men undergoing early salvage RT are presented separately. (See "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management", section on 'Prostate bed RT plus androgen deprivation therapy'.)

Data from randomized trials established the benefit of combining external beam RT and concurrent ADT for men undergoing RT as the primary treatment for clinical (c) T3 prostate cancer, as well as for those with lower stage but "high-risk" disease (ie, Gleason score 8 to 10, PSA >20 ng/mL). (See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement", section on 'Role of concurrent ADT'.)

The benefit of adding ADT to adjuvant RT is uncertain. The trials of early salvage versus adjuvant RT discussed above did not address the relative contribution of ADT; the use of ADT was variable in all three trials. (See 'RT: adjuvant versus early salvage' above.)

Two trials from the RTOG (RTOG trials 9601 and 0534) provide additional information about the use of concurrent ADT in men with a rising PSA following radical prostatectomy (ie, early salvage rather than adjuvant RT); neither provides a definitive answer as to the benefit of ADT with adjuvant RT. These trials are discussed in detail elsewhere. (See "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management", section on 'Prostate bed RT plus androgen deprivation therapy'.)

ADT alone without radiation therapy — The role of adjuvant ADT alone after prostatectomy is uncertain. We reserve this approach (typically high-dose bicalutamide [150 mg daily]) as an alternative to adjuvant RT for a very select population of sexually active young men who have preserved erectile function after radical prostatectomy for high-risk, completely resected disease (eg, Gleason score ≥7, pT3b), who are aware of the risk of gynecomastia, and who wish to avoid RT. These men derive less benefit from adjuvant RT than those with extraprostatic extension (pT3a) because of their high rates of systemic relapse. Although no study has adequately examined the necessary length of adjuvant hormone therapy, the empiric recommendation is for a total of two years.

There are only limited data about the role of adjuvant hormone therapy without RT after radical prostatectomy for patients who are found to have pT3 disease [33,34].

The uncertain role of adjuvant hormone therapy without RT is illustrated by the following examples:

●In a retrospective, nonrandomized cohort of men who underwent radical prostatectomy for pathologic node-negative prostate cancer at the Mayo Clinic between 1990 and 1999, 580 men received adjuvant ADT, while 1160 were managed expectantly without adjuvant ADT [33]. Overall, approximately 55 percent of the men had a T3 or T4 primary tumor. Of those managed without adjuvant therapy, 343 (30 percent) subsequently received ADT for either a biochemical or systemic recurrence.

Adjuvant ADT was associated with statistically significant improved rates of 10-year biochemical and systemic progression-free survival compared with delayed treatment (95 versus 90 and 98 versus 95 percent, respectively). However, there was no improvement in overall survival (84 versus 83 percent).

●The addition of high-dose bicalutamide monotherapy (150 mg daily) to watchful waiting, radical prostatectomy, or RT was extensively evaluated in the Early Prostate Cancer program in 8113 men with localized (T1, T2) or locally advanced (T3, T4), non-metastatic prostate cancer [34]. At a median follow-up of 10 years, treatment with bicalutamide was associated with a statistically significant improvement in progression-free survival in men with locally advanced (T3, T4) disease, regardless of the initial management approach. However, there was no statistically significant difference in overall survival in these patients. The results in the 2734 men with locally advanced prostate cancer managed initially with radical prostatectomy also showed a statistically significant benefit in progression-free survival but not overall survival. The dose of bicalutamide used in these trials (150 mg daily) was three times the approved dose.

Role of chemotherapy — The available evidence that any form of chemotherapy (docetaxel, mitoxantrone) is beneficial in the adjuvant setting is insufficient to routinely recommend this practice.

Adjuvant chemohormonal therapy — Clinical trials have shown a benefit from combining docetaxel chemotherapy with ADT in combined populations of men with metastatic, recurrent, high-risk, or locally advanced disease who are starting long-term hormone therapy (the STAMPEDE trial [35]).

On the other hand, at least three trials have explored the benefit of adding chemotherapy to ADT plus adjuvant RT in men with high-risk resected prostate cancer, and the results are conflicting:

●A potential benefit for adding docetaxel to RT and six months of ADT for men with either a post-radical prostatectomy PSA nadir >0.2 ng/mL and a Gleason score ≥7, or a PSA nadir ≤0.2 ng/mL, a Gleason score ≥8, and a pT classification ≥pT3 was suggested in the NRG Oncology/RTOG 0621 trial [36]. The three-year freedom from progression rate was 73 percent, and three-year cumulative incidence rates of biochemical, distant, and local failure were 26, 7, and 0 percent, respectively. Although these rates compared favorably with historical series, there was no control group receiving only RT and six months of ADT for comparison.

●On the other hand, a benefit for adding mitoxantrone plus prednisone to ADT following radical prostatectomy for high-risk disease (including T3/T4 tumors, positive margins, or grade group 4 or 5 (table 3)) could not be shown in the phase III SWOG trial S9921 [37].

Additional information on benefit of adjuvant chemohormonal therapy can be extrapolated from the following studies:

●A French trial showed that combined ADT plus docetaxel did not significantly improve PSA progression-free survival compared with ADT alone in men with high-risk prostate cancer, rising PSA levels, and no evidence of metastatic disease [38]. (See "Role of systemic therapy in patients with a biochemical recurrence after treatment for localized prostate cancer", section on 'ADT plus abiraterone, docetaxel, or apalutamide'.)

●Benefits from adjuvant chemohormonal therapy were also observed in the RTOG 0521 trial, in which 563 evaluable patients were treated with ADT for two years beginning two months prior to RT (72 to 75 Gy) [39]. Those randomly assigned to chemotherapy also received docetaxel (75 mg/m²) plus prednisone for six cycles beginning one month after the completion of RT. All patients had high-risk disease: median serum PSA was 15 ng/mL, 53 percent had Gleason 9 or 10 disease, and 27 percent had clinical T3 or T4 disease. Overall survival was improved with adjuvant chemotherapy compared with ADT alone. (See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement", section on 'Role of chemotherapy'.)

Additional follow-up and information from these and other trials (eg, NCT03070886) will be required to determine the role of chemohormonal therapy in the adjuvant setting.

Adjuvant docetaxel chemotherapy — There is no evidence that adjuvant docetaxel with or without ADT is beneficial in an adjuvant setting. In a randomized phase III trial, the addition of docetaxel to RT without hormonal therapy did not significantly improve biochemical disease-free survival [40] following radical prostatectomy for unfavorable-risk prostate cancer.

Persistently elevated prostate-specific antigen — For patients in whom the serum PSA falls to undetectable levels following definitive surgery, careful monitoring is indicated, including a serum PSA every three to six months. For men who have a persistently detectable serum PSA level following radical prostatectomy, the role of early, rather than deferred, ADT in conjunction with RT is unclear. Although most of these men have occult metastatic disease, RT can cure a small but consistent fraction of these men. The role of salvage RT after radical prostatectomy is discussed elsewhere. (See "Follow-up surveillance after definitive local treatment for prostate cancer".)

If the PSA remains detectable or subsequently rises, patients are presumed to have residual disease. Such patients should be evaluated for evidence of local recurrence and metastatic disease depending on the level and rate of rise of the PSA. Subsequent management is guided by this evaluation. (See "Rising serum PSA following local therapy for prostate cancer: Diagnostic evaluation" and "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management".)

LYMPH NODE INVOLVEMENT — For most men with pathologic lymph node involvement and an undetectable PSA following surgery, we suggest adjuvant androgen deprivation therapy (ADT) with or without radiation therapy (RT). The optimal duration of ADT is not established; we aim for 24 to 36 months of therapy. (See 'Adjuvant androgen deprivation therapy' below.)

For men who have an estimated life expectancy of at least five years, we prefer adjuvant ADT with RT. However, individual values and preferences are an important component of this decision, and many individuals decline RT, particularly if the PSA is undetectable after surgery. If RT is chosen, many clinicians, including some of the authors and editors associated with this review, delay initiation until 6 to 12 months postoperatively. (See 'Adjuvant radiation therapy' below.)

Although National Comprehensive Cancer Network (NCCN) guidelines suggest observation as an option in this setting, we do not favor this approach for most men. However, men who place a higher value on quality of life issues and are willing to accept the uncertainty of oncologic outcomes might reasonably choose close PSA monitoring and deferral of ADT and RT until a biochemical recurrence develops.

With the increased use of radical prostatectomy and extended pelvic lymph node dissection as the initial treatment for men with intermediate- and high-risk prostate cancer, increased numbers of men are being diagnosed with microscopic lymph node involvement. Furthermore, there is concern that an increasing number of men undergoing radical prostatectomy will have more advanced disease when their prostate cancers are diagnosed because of changes in recommendations for PSA screening [41]. (See "Screening for prostate cancer", section on 'PSA testing' and "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement", section on 'Radical prostatectomy'.)

The optimal management of men with node-positive disease diagnosed at radical prostatectomy is not clearly established; there is a paucity of randomized trials in this area.

Risk of recurrence — The presence of lymph node metastases is frequently associated with the eventual development of disseminated, systemic disease. However, outcomes are quite variable, and pathologically positive lymph nodes are not universally associated with rapid progression to prostate cancer-related death [42-48]. In many patients, a combined approach to therapy that includes both hormonal and radiotherapeutic interventions may be associated with prolonged relapse-free survival and long-term survival. (See 'Lymph node involvement' above.)

As an example, a single-institution study analyzed 1011 men with one or more positive lymph nodes identified at radical prostatectomy who were treated between 1987 and 2012 [42,43]. In this series, 88 percent of patients received adjuvant hormone therapy, and 9 percent received adjuvant RT. Median follow-up was 17.6 years. The rate of biochemical recurrence at 15 years was 52 percent, and the rate of clinical recurrence was 33 percent. Approximately one-half of the clinical recurrences were detected more than five years after surgery. Factors associated with an increased risk of clinical recurrence on multivariate analysis included the presence of three or more positive lymph nodes, Gleason score 8 to 10 disease, the omission of adjuvant RT, and positive surgical margins.

Based on these data, a risk score was created using the number of positive nodes, the histologic grade group (table 3), the margin status, and the adjuvant RT status that successfully separated patients into low-, intermediate-, and high-risk groups with 10-year cancer-specific mortality rates of 6, 16, and 27 percent, respectively [43].

Adjuvant androgen deprivation therapy — Adjuvant ADT appears to decrease cancer-specific mortality and the incidence of biochemical recurrence and distant metastases in men with positive lymph nodes at radical prostatectomy. Benefit for early adjuvant ADT was shown in a trial in which 98 men were randomly assigned to ADT immediately following prostatectomy or to observation with ADT given for distant metastases or symptomatic recurrences [49,50]. In the latest analysis, with a median follow-up of 12 years, patients assigned to immediate rather than delayed ADT had significant improvements in overall survival (hazard ratio [HR] 1.84, 95% CI 1.01-3.35), prostate cancer-specific survival (HR 4.09, 95% CI 1.76-9.49), and progression-free survival (HR 3.42, 95% CI 1.96-5.98).

In our view, further support for the benefit of adjuvant ADT comes from the SWOG S9921 trial, in which 961 men who underwent prostatectomy for clinical T1-3N0 prostate cancer with one or more risk factors (including pathologically positive nodes, which were present in 17 percent of enrollees) were randomly assigned to ADT with or without mitoxantrone and prednisone [37]. Approximately one-fourth of the patients in each group also received adjuvant RT. Despite the high-risk nature of the cohort, the 10-year overall survival estimate for the ADT group was 87 percent, and prostate cancer was the cause of death in only 8 percent. (See 'Adjuvant chemohormonal therapy' above.)

Adjuvant radiation therapy — We suggest adjuvant external beam RT plus ADT for men with lymph node involvement and an estimated life expectancy of more than five years; for others, observation or ADT alone are options. However, individual values and preferences are an important component of this decision, and many men decline RT, particularly if the PSA is undetectable after surgery. If RT is chosen, many clinicians, including some of the authors and editors associated with this review, delay initiation until 6 to 12 months postoperatively.

There are no large randomized trials assessing the role of adjuvant RT following radical prostatectomy in men with positive lymph nodes. However, retrospective data from large series suggest that this approach can improve outcomes in some individuals:

●This issue was addressed in a retrospective cohort study of 1338 men with positive lymph nodes who underwent radical prostatectomy at three centers between 1988 and 2010, which analyzed overall survival for those whose initial management was observation (n = 387), ADT (n = 676), or RT plus ADT (n = 325) [51]. There were substantial differences in the patient populations managed with different strategies, with a higher pathologic Gleason score, higher pathologic stage of the tumor, and higher number of involved lymph nodes being more likely to receive aggressive adjuvant therapy.

The combination of ADT plus RT was associated with a significantly improved overall survival compared with observation (HR 0.41, 95% CI 0.27-0.64) or ADT alone (HR 0.46, 95% CI 0.32-0.66). The 10-year all-cause mortality with ADT plus RT ranged from 12 to 31 percent based on pathologic Gleason grade, stage, margin status, and the number of positive nodes. For those managed with ADT alone, the 10-year all-cause mortality ranged from 17 to 71 percent based on associated risk factors.

●As noted above, a benefit for adjuvant rather than early salvage RT for men with high-risk disease, including those with pN1 disease was also suggested in a multi-institutional analysis of 26,118 men with pT2-3N0 or N1M0 prostate cancer who were consecutively treated with radical prostatectomy and pelvic lymphadenectomy at one of four medical centers in the United States and Germany [17]. In an adjusted analysis, and after excluding men with a persistently positive PSA level, adjuvant RT significantly reduced all-cause mortality compared with early salvage RT in men with adverse pathologic features, including those with pN1 disease (relative risk [RR] 0.66, 95% CI 0.44-0.99) or without pN1 disease (RR 0.33, 95% CI 0.13-0.85). (See 'Men with high-risk disease' above.)

At least some data suggest that the beneficial impact of adjuvant RT on men with pathologic node-positive disease is influenced by other tumor characteristics:

●In a retrospective analysis of 1107 men with pathologic (p) N1 prostate cancer treated with radical prostatectomy over a 22-year period at two tertiary cancer centers, RT improved cancer-specific mortality in only two groups: men with two or fewer positive lymph nodes and intermediate- to high-grade non-specimen-confined disease (ie, Gleason score 7 to 10 disease, pT3b/pT4 stage, or positive surgical margins), or men with three or four positive lymph nodes [52].

●A second analysis concluded that adjuvant RT benefitted only patients with at least two of the following pathologic features after radical prostatectomy: grade group 4 or 5 disease (table 3), pT3/pT4 disease, and positive lymph nodes [53].

SURVEILLANCE AFTER TREATMENT — Surveillance strategies after treatment for localized prostate cancer are discussed separately. (See "Follow-up surveillance after definitive local treatment for prostate cancer".)

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic

SUMMARY AND RECOMMENDATIONS

●pT3 or margin-positive disease

•In contemporary series, between 50 and 75 percent of men with pathologic (p) T3 disease will ultimately have a biochemical relapse following radical prostatectomy. The risk of a disease recurrence in men with positive margins or pathologically positive lymph nodes is variable. (See 'Risk of recurrence' above.)

•Despite the uncertainty of benefit for RT, the following represents our approach to adjuvant treatment in these patients:

-For men with pT3 disease, negative nodes, negative or minimally positive surgical margins following radical prostatectomy, and an undetectable serum PSA, we suggest early salvage RT at the first sign of PSA recurrence rather than adjuvant RT (Grade 2B). (See 'RT: adjuvant versus early salvage' above.)

-For the occasional man with extensively positive surgical margins, especially with grade group 4 or 5 disease (table 3) we discuss the risks and benefits of adjuvant external beam RT following radical prostatectomy, for shared decision-making. Careful monitoring for evidence of a biochemical recurrence, followed by salvage RT at the earliest evidence of relapse, is an acceptable alternative. (See 'Men with high-risk disease' above.)

-Outside the context of a clinical trial, we do not administer ADT to men undergoing adjuvant RT. Specific recommendations for concurrent ADT in men undergoing early salvage RT are presented separately. (See "Rising or persistently elevated serum PSA following radical prostatectomy for prostate cancer: Management", section on 'Prostate bed RT plus androgen deprivation therapy'.)

-The role of adjuvant ADT alone after prostatectomy with node-negative disease is uncertain. We reserve this approach (typically high-dose bicalutamide [150 mg daily]) for a very select population of sexually active young men who have preserved erectile function after radical prostatectomy for high-risk, completely resected disease (eg, grade group 4 or 5 (table 3), pT3b) with an undetectable PSA, who are aware of the risk of gynecomastia, and who wish to avoid RT. (See 'ADT alone without radiation therapy' above.)

-We do not administered any form of chemotherapy (docetaxel, mitoxantrone) in the adjuvant setting, as there is no evidence to suggest benefit. (See 'Role of chemotherapy' above.)

●Positive lymph nodes

•For most men with pathologic lymph node involvement and an undetectable PSA following surgery, we suggest adjuvant ADT with or without RT (Grade 2B). The optimal duration of ADT is not established; we aim for 24 to 36 months of therapy.

For most patients with pathologic lymph node involvement who have an estimated life expectancy of at least five years, we prefer adjuvant ADT with RT. However, individual values and preferences are an important component of this decision, and many individuals decline RT, particularly if the PSA is undetectable after surgery. If RT is chosen, many clinicians, including some of the authors and editors associated with this review, delay initiation until 6 to 12 months postoperatively.

Although National Comprehensive Cancer Network guidelines suggest observation as an option in this setting, we do not favor this approach for most men. However, men who place a higher value on quality of life issues and are willing to accept the uncertainty of oncologic outcomes might reasonably choose close PSA monitoring and deferral of ADT and RT until a biochemical recurrence develops. (See 'Lymph node involvement' above.)

ACKNOWLEDGMENT — We are saddened by the death of Nicholas Vogelzang, MD, who passed away in September 2022. UpToDate acknowledges Dr. Vogelzang's past work as an author for this topic.