Narrative review of management strategies and outcomes in node-positive prostate cancer

Introduction

Approximately 13% of the 191,930 patients newly diagnosed with prostate cancer in the United States in 2020 will present with metastasis to the regional lymph nodes (N1M0) (1). In the current American Joint Committee on Cancer (AJCC) 8^th edition staging manual, metastasis to pelvic lymph nodes (pelvic, hypogastric, obturator, iliac, sacral) are classified as N1, and are group stage IV-A (2). Historically, clinicians have grouped prostate cancer that have metastasized to lymph nodes together with distant metastasis in the same category of advanced prostate cancer. However, evolving data now support the management of N1M0 patients akin to locally advanced prostate cancer, including the use of multimodality therapy to reduce recurrence, improve survival, and potentially cure a portion of patients. Due to a paucity of randomized evidence in this area, the management of this patient population varies widely in clinical practice. This article reviews the relevant studies that have shaped the modern management of node-positive prostate cancer patients and summarizes their associated outcomes. We present the following article in accordance with the Narrative Review reporting checklist (available at http://dx.doi.org/10.21037/tau-20-1031).

Management of clinically node-positive, nonmetastatic (cN1M0) prostate cancer

Androgen deprivation therapy (ADT) without local therapy

ADT historically was an accepted treatment for patient with cN1M0 prostate cancer. This follows the paradigm for patients with metastatic prostate cancer (M1) where ADT is the long-established standard of care. ADT in node-positive patients is generally initiated at the time of diagnosis rather than delayed. The randomized EORTC 30846 trial evaluated the non-inferiority of delayed ADT compared to immediate ADT in 234 patients diagnosed with nodal disease by biopsy or staging lymphadenectomy (Table 1) (3).

Table 1 Studies evaluating ADT and systemic treatments for node-positive prostate cancer
Full table

No local treatment was offered to the primary tumor. The intent-to-treat analysis showed a 22% [hazard ratio (HR): 1.22; 95% CI: 0.92–1.62] increase in the hazard of death with delayed ADT, though this did not reach statistical significance. Median overall survival (OS; 7.6 vs. 6.1 years) and 10-year cancer-specific survival (CSS; 47.9% vs. 44.4%) were not statistically significantly different between the immediate and delayed ADT arms. This trial was unable to demonstrate non-inferiority of delayed ADT, thus starting ADT at the time of diagnosis remains the standard of care.

Intermittent ADT has not specifically been studied in cN1M0 patients, so its use is not recommended. The SWOG 9346 trial randomized newly diagnosed M1 patients to continuous versus intermittent ADT (7), and was unable to conclude non-inferiority of intermittent ADT by excluding 20% increased risk of death with intermittent ADT. However, the applicability of results from this trial to patients with cN1M0 disease is unclear.

For M1 patients, several large randomized trials demonstrated improvement in OS with the addition of advanced hormonal therapy (e.g., abiraterone, enzalutamide, apalutamide) to ADT in hormone sensitive metastatic prostate cancer (8-10). However, none of these trials specifically studied cN1M0 patients. The STAMPEDE trial investigated the addition of abiraterone to ADT in a heterogenous population of men with M1 (53%), N1M0 (20%), or localized high risk prostate cancer (27%) (4). Local therapy with radiotherapy was optional for N1M0 patients. Abiraterone improved failure-free survival (FFS) in the overall study population (HR: 0.29; P<0.001) with similar effect on the N1 (HR: 0.29) and M0 (HR: 0.21) patient subsets. However, N1M0 patients were not specifically analyzed. Abiraterone was also associated with improved OS for the overall study population (HR: 0.63; 95% CI: 0.5–0.76; P<0.001) and on subset analysis for patients with any nodal dissemination (HR: 0.61; 95% CI: 0.48–0.77). Again, data for N1M0 patients were not separately analyzed. This study suggests but does not clearly demonstrate that the addition of abiraterone to standard ADT improves cancer control or survival outcomes in N1M0 patients.

ADT + radiation therapy (RT)

Definitive RT for cN1M0 prostate cancer most commonly covers the pelvic nodal regions, prostate and seminal vesicles. In randomized clinical trials, adding RT to ADT has demonstrated an improvement in survival in patients with high-risk localized disease (less advanced than N1M0 disease) and also in hormone sensitive M1 disease (more advanced than N1M0). Two large randomized trials compared indefinite ADT alone vs. ADT + RT in patients with high risk localized prostate cancer. The SPCG-7 reported a dramatic reduction in prostate-specific antigen (PSA) recurrence (HR: 0.16; 95% CI: 0.12–0.20; P<0.0001) and improved prostate CSS (HR: 0.44; 95% CI: 0.30–0.66; P<0.001) (11) from the addition of RT. NCIC PR.3 reported similar improvement in prostate CSS (HR: 0.46; 95% CI: 0.34–0.66; P<0.001) (12). In hormone sensitive M1 prostate cancer, the H-arm of the STAMPEDE trial compared ADT + prostate RT to ADT alone (13). In a pre-specified subset analysis of patients with low metastatic burden, the addition of prostate RT improved both FFS (HR: 0.59; 95% CI: 0.49–0.72; P<0.001) and OS (HR: 0.65; 95% CI: 0.47–0.90; P=0.01). Of note, node-positive prostate cancer is a disease state between localized and metastatic prostate cancers. Extrapolation of improved survival from these randomized trials in patients with less advanced (high risk localized) and more advanced (low volume M1) prostate cancer provides a rationale for the potential benefit of adding RT to ADT for N1M0 positive cancer.

Retrospective series also provide evidence for the role of RT in cN1M0 prostate cancer. With caveats of potential uncontrolled confounders and selection bias, these studies have consistently demonstrated improvements in both cancer control and survival outcomes (Table 2). One prospective randomized trial, RTOG 9608, attempted to compare RT and ADT versus ADT alone in node-positive patients but it was terminated early due to poor accrual.

Table 2 Studies evaluating definitive radiotherapy for node-positive prostate cancer
Full table

The largest single institution series from the MD Anderson Cancer Center retrospectively evaluated 255 men with pelvic nodal metastases identified on staging pelvic lymphadenectomy treated with either ADT alone or ADT + RT (14). ADT consisted of orchiectomy or medical castration. External beam radiotherapy (EBRT) was delivered to the prostate in 72 patients, with doses ranging from 60–78 (median 68) Gy. After a median follow-up of 6.2 (ADT + RT) to 9.4 (ADT alone) years, patients who received ADT + RT demonstrated superior 10-year OS (46% vs. 67%; P=0.008), local control (LC) (49% vs. 89%; P<0.001), freedom from biochemical relapse (25% vs. 80%; P<0.001), and freedom from distant metastasis (FFDM) (56% vs. 85%; P=0.006).

An unplanned analysis of N1M0 patients from the control arm of the STAMPEDE trial also support the addition of RT (18). All patients received ADT on the control arm of the trial, and RT was optional for N1M0 patients. Of the 157 patients included in the analysis, 45% (n=71) received RT to doses at discretion of the treating physician. The addition of RT to ADT was associated with higher 2-year FFS (89% vs. 64%; HR: 0.35; 95% CI: 0.19–0.65) after adjusting for Gleason score, PSA, age and performance status. OS data have not yet been presented.

Population and hospital-based studies have also reported improvement in OS with the use of RT in patients with N1M0 prostate cancer. Tward et al. used the Surveillance Epidemiology & End Results (SEER) database to compare outcomes in node-positive patients diagnosed from 1988–2006 who received RT versus no local therapy. On multivariable analysis, RT was associated with an improvement in CSS (HR: 0.67; 95% CI: 0.54–0.84; P<0.01); 10-year CSS results were 50.3% vs. 62.7% (15). Similar results were noted by Rusthoven et al. in a separate SEER study of local therapy for node-positive cancer (16). Of note, the use of ADT was not recorded in the SEER and is a major limitation to these analyses. An analysis of the National Cancer Database (NCDB) compared OS in a propensity matched cohort of 636 node-positive patients receiving ADT alone (n=318) or ADT + RT (n=318) (17). Of those receiving RT, 97% received RT with median doses of 50.4 Gy to the pelvis and 75.6 Gy total. The use of combined ADT + RT was associated with an approximately 50% reduction in all-cause mortality at 5 years compared to ADT alone (HR: 0.50; 95% CI: 0.37–0.67; P<0.001).

Overall, the published evidence including clinical trials and retrospective studies support the addition of prostate RT to ADT for the treatment of cN1M0 patients.

ADT + radical prostatectomy (RP) with extended pelvic lymph node dissection (ePLND)

The evidence for definitive surgery for patients with known nodal disease is limited. RP with or without PLND is one standard of care in patients with localized prostate cancer. However, for clinically node-positive disease, the use of RP remains controversial. The EAU-ESTRO-SIOG allows for RP with ePLND in very selected patients, whereas this is not a recommendation in the NCCN guidelines (Table 3).

Table 3 Current guidelines on the management of N1M0 prostate cancer
Full table

Historically, planned prostatectomies have been abandoned for futility upon finding of lymph node metastasis during the lymph node dissection (24). This perspective has been challenged with multiple retrospective series which have reported improvement in survival with RP in node-positive prostate cancer (see section “Management for pathologically node-positive prostate cancer”). It is important to note a distinction between clinical node-positive (cN+) and pathologic node-positive (pN+) prostate cancer. Many of the patients with pathologically detected lymph node metastasis after PLND had clinically negative nodes (cN0) pre-operatively.

Data on the role of prostatectomy in cN+ patients are limited. Seisen et al. used the NCDB to compare outcomes in cN1M0 patients treated with ADT versus RP + ADT, and reported an improvement in 5-year OS from 49.2% to 78.8% (HR: 0.31; 95% CI: 0.13–0.74; P=0.007) (25). This study also compared outcomes of ADT + RT, and found ADT + either RP or RT had similar improvements compared to ADT alone. These data suggest that local therapy, regardless of modality, may confer a survival improvement compared to ADT alone.

RT ± ADT

Randomized data suggest that local therapy alone is not sufficient for patients with node-positive cancer. Multiple randomized studies have demonstrated improvements in OS, biochemical control, and distant failure when ADT is added to RT for localized and locally advanced prostate cancers (19,20,26-28). Two smaller trials specifically provide data related to RT vs. RT + ADT in node-positive disease (Table 2). The RTOG 8531 trial randomized 977 patients with either nodal metastasis or clinical T3 prostate cancer to RT + ADT versus RT alone. Post-prostatectomy patients were allowed if they contained pT3 disease or involved margins. A subgroup analysis of patients with node-positive prostate cancer (n=173) showed that combination RT + ADT was associated with improved absolute survival (P=0.03), cause-specific failure (P=0.014), metastatic failure (P=0.0005), and biochemical control (P<0.0001) compared to RT alone (19). A Swedish trial randomized node-positive patients to RT or RT plus orchiectomy (20). Initially planned for 400 patients, the study closed early after 91 patients when interim analysis showed significant rates of disease progression in the RT alone arm. Combined modality therapy showed a significant OS benefit (P=0.005) at a median follow-up of 9.7 years. These data established the need to add ADT to RT for this patient population.

The optimal duration of ADT with definitive RT in the cN1M0 setting is not established. Clinicians have commonly extrapolated from trials of locally advanced prostate cancer to offer 2–3 years of ADT (29,30).

Chemotherapy

The role of chemotherapy in the primary management of node-positive prostate cancer is controversial. The addition of chemotherapy improves survival in patients with castrate-sensitive M1 prostate cancer, a disease state that is more advanced than N1M0 prostate cancer, though this benefit may be limited to patients with high volume disease (31). Data for chemotherapy in patients with N1M0 cancer are limited. Patients with node-positive cancer have been included in two randomized trials evaluating the addition of chemotherapy (Table 1). GETUG AFU-12 randomized 413 patients with N1M0 (29%) or high-risk N0M0 prostate cancer (71%) to receive either 3 years of ADT plus four cycles of docetaxel and estramustine, or ADT alone (5). Almost all patients also received local therapy. The primary endpoint of relapse-free survival (RFS) at 8 years was improved with ADT plus chemotherapy compared to ADT alone (62% vs. 50%; adjusted HR: 0.71; 95% CI: 0.54–0.94; P=0.017). OS at 8 years was 83% for both arms combined; however, there were too few events to analyze the N1M0 and N0M0 groups separately. No subgroup analysis was reported for patients with N1M0 disease.

The STAMPEDE trial randomized 2,962 prostate cancer patients to ADT alone, ADT plus six cycles of docetaxel, ADT plus zoledronic acid, or ADT plus docetaxel and zoledronic acid (6). Eligible patients were diagnosed with either M1 (61%), N1M0 (15%), or localized prostate cancer with at least two high-risk features (24%). Radiotherapy was optional for N1M0 patients. OS (median 60 vs. 45 months; HR: 0.78; 95% CI: 0.66–0.93; P=0.005) and FFS (median 44 vs. 35 months; 95% CI: 0.53–0.70; P<0.001) were improved with the addition of docetaxel to ADT. On subset analyses of patients with M0 disease, docetaxel was associated with an improvement in FFS but not OS. A subset analysis of N1M0 only patients was not performed.

Based on these results, there is currently no clear role for chemotherapy for N1M0 prostate cancer.

Management for pathologically node-positive prostate cancer

RP and lymph node dissection

Retrospective surgical series with long-term follow-up suggest a beneficial impact of RP compared to no local therapy on both overall and CSS for patients with node-positive prostate cancer (24,32,33). One large German cohort compared outcomes of patients with intraoperative finding of lymph node metastasis where the prostatectomy was abandoned versus completed (24). Completion prostatectomy was associated with an improvement in 5-year OS from 60% to 84% (HR: 2.04; 95% CI: 1.59–2.63; P<0.0001). In multiple series, the reported 10-year outcomes of pN+ patients after RP and PLND without further adjuvant local therapy are approximately 60–66% OS and 70–85% CSS; however, only a third of patients remained free of biochemical progression (24,32-37).

In highly selected pN+ patients with favorable disease characteristics, outcomes after surgery alone may be more favorable. A series from Mayo Clinic reported 10-year CSS as high as 94% for patients with only one positive lymph node (35). Another series reported that patients with fewer than three positive nodes and Gleason grade group 1–3 had less than a 10% risk of clinical recurrence at 8 years (38). However, it should be noted a majority of patients included in these studies received adjuvant therapies in addition to surgery. A series from Memorial Sloan Kettering Cancer Center reported 5- and 10-year freedom from biochemical recurrence of 35% and 28% following prostatectomy alone without adjuvant therapy (37). Gleason score of 8–10, multiple positive nodes, positive surgical margins, and a low total number of lymph nodes removed have been identified as predictors of higher post-prostatectomy recurrence and cancer-specific mortality (CSM) for patients with pN+ disease (36,37,39,40).

While selected pN+ patients with favorable disease can achieve long term biochemical control with surgery alone, the addition of adjuvant therapy with ADT or ADT + RT can improve survival and is generally recommended. The following sections will review the data for these approaches.

Adjuvant ADT

The role of adjuvant ADT after RP and PLND for node-positive patients was established by the ECOG 3886 trial (41). Messing et al. randomized 98 patients found to have pathologic node-positive cancer after RP to immediate continuous ADT (n=47) or deferred ADT (n=51) until the development of metastasis or symptomatic recurrence. Immediate ADT was initiated within 12 weeks of surgery. Compared to delayed ADT, immediate adjuvant ADT was associated with superior OS (median OS 11.3 vs. 13.9 years; P=0.04) and CSS (median CSS 12.3 years vs. not reached for immediate ADT; P=0.0004) after 11.9 years of median follow-up. Despite its small sample size, ECOG 3886 provides the only level 1 evidence to date to guide adjuvant treatment for pN+ disease.

Retrospective data have been mixed. Results from a SEER-Medicare analysis of 731 men did not show a survival improvement with adjuvant ADT within 120 days of surgery compared to observation (42). After propensity score matching, there was no difference in OS (HR: 0.95; 95% CI: 0.71–1.27) or CSM (HR: 0.97; 95% CI: 0.56–1.68) from adjuvant ADT compared to no immediate treatment. A multi-institutional comparative analysis demonstrated improved CSM with adjuvant ADT compared to surgery alone (HR: 3.05; 95% CI: 1.45–6.40; P=0.003), but OS was not improved (43). Nonetheless, based the randomized Messing data, adjuvant ADT remains a standard of care. While the ECOG 3886 trial was designed for lifelong ADT, in actual clinical practice, stopping ADT at 2 years is common. The optimal duration of adjuvant ADT in pN+ patients has not been studied prospectively.

Adjuvant ADT + RT

Many patients found to have pN+ prostate cancer experience disease progression despite RP and adjuvant ADT (34,39). Isolated locoregional recurrences after RP were observed in 31% of patients experiencing clinical progression in one series (44). No randomized trial has assessed the use of adjuvant RT for pN+ patients. There are several retrospective studies which have demonstrated improved OS, CSS, and biochemical relapse-free survival (BCRFS) with the addition of adjuvant RT (Table 4).

Table 4 Studies evaluating RP and adjuvant therapies for pathologically node-positive prostate cancer
Full table

A single institution series of 250 patients found that adjuvant RT was independently associated with improved CSS and BCRFS compared to adjuvant ADT alone for patients with pN+ disease (45). A matched retrospective analysis contained 364 pN1 patients who received either adjuvant ADT (n=247) or adjuvant RT + ADT (n=171) after surgery (46). The addition of adjuvant RT improved both CSS (10-yr CSS: 86% vs. 70%; P=0.004) and OS (10-yr OS: 74% vs. 55%; P<0.001) after matching for patient age, Gleason score, pathologic T stage, extent of nodal dissection, and follow-up length. Touijer et al. published the largest multi-institutional series to date comparing of outcomes from 1,338 pN+ patients managed with observation after RP (n=387), RP plus ADT (n=676), or RP plus ADT + RT (n=325) (43). The adjuvant ADT + RT group contained patients with higher pathologic stages and Gleason scores. Despite this, combined adjuvant ADT + RT was associated with a lower risk of all-cause mortality (HR: 0.46; 95% CI: 0.32–0.66; P<0.0001) and CSM (HR: 0.41; 95% CI: 0.27–0.64; P<0.0001) compared to adjuvant ADT. Similarly, adjuvant ADT + RT was associated with improved survival compared to observation after surgery.

Patient selection may be important when considering adjuvant radiation. Abdollah et al. compared outcomes of adjuvant ADT versus ADT + RT stratified by clinical risk factors: number of lymph nodes, Gleason score, and pathologic local extension (47). These risk features were used to stratify pN+ patients in to five risk groups. In this analysis, only two of the five risk group subsets benefitted from the addition of RT in terms of 8-year prostate CSS: (I) patients with 3–4 positive lymph nodes; and (II) patients with 1–2 positive lymph nodes and Gleason score ≥7, plus either stage pT3b-T4 or positive surgical margins. Patients with more positive nodes or lower risk disease did not demonstrate a survival benefit in this retrospective analysis. A separate study used data from the NCDB to confirm the external validity of the Abdollah et al. study, and replicated the observation that adjuvant RT only benefitted patients with 3–4 positive nodes or patients with 1–2 positive nodes plus additional adverse pathological features (52). Another analysis of the NCDB data demonstrated that the survival benefit of adjuvant RT was only apparent for patients with at least one adverse pathological feature: ≥3 positive nodes, stage pT3b-4 disease, Gleason score ≥9, or positive margins (51).

Overall, existing studies suggest that for patients with pN+ disease, adding RT to adjuvant ADT likely improves long-term outcomes including survival, at least for some subgroups of pN+ patients with certain characteristics. Accordingly, the EAU guidelines (grade A) and NCCN guidelines (category 2B) recommend adjuvant RT plus ADT for pN+ patients (Table 3).

Timing of post-prostatectomy therapy

In general, the timing of post-prostatectomy therapy for pN+ patients has been guided by the ECOG 3886 trial, which initiated ADT within 12 weeks of prostatectomy.

In select patients with pN+ cancer after RP and undetectable post-operative PSA, observation without immediate adjuvant therapy is a potential option as described in the EAU guidelines (Grade B) and NCCN guidelines (no category recommendation) (Table 3). In these patients, whether initial observation followed by treatment at the time of biochemical recurrence (“early salvage”) may be equally effective compared to immediate adjuvant therapy is unknown. In one large retrospective study in pN+ patients, the use of adjuvant ADT + RT was associated with an improvement in OS (HR: 0.41; P<0.001) compared observation and salvage therapy at recurrence (43). The recently reported results from the RAVES (53) and RADICALS (54) randomized trials—which found equivalent control between adjuvant RT and early salvage RT in mainly early-stage prostate cancer patients after RP—should not be extrapolated to pN+ patients who constitute a much higher risk population than those studied in the trials.

Conclusions

There is currently limited randomized evidence to define the optimal treatment strategy for men with node-positive prostate cancer. The studies reviewed in this article provide a rationale for a multimodality treatment approach. For patients with cN1M0 prostate cancer, one standard option is definitive RT with long-term ADT, and another option is RP. For patients with pN+ disease after RP, adjuvant ADT is supported by the ECOG 3886 trial. Adjuvant ADT + RT is another option supported by retrospective studies suggesting that it may improve survival compared to adjuvant ADT alone. For select pN+ patients, observation could also be considered. Current international guideline recommendations for both cN1M0 and pN+ diagnoses are summarized in Table 3.

The outcomes summarized here are reflective of a heterogenous population contained in mostly retrospective studies which have methodological limitations. More clinical trials are needed for this understudied patient population to provide high-quality evidence to guide treatment decision-making. One such trial is NRG GU008 (NCT 04134260), which for patients with pN+ disease after RP is comparing salvage RT + ADT vs. RT + ADT + abiraterone and apalutamide. Intensifying treatment for this group of patients with stage IV disease is likely needed to maximize long-term survival and the potential for cure. Of note, the incidence of node-positive prostate cancer at diagnosis is currently increasing, coincident with decreased PSA screening and enhanced ability to detect occult nodal metastases with new imaging modalities such as the FACBC, choline and prostate-specific membrane antigen PET scans (55). This increase may provide an opportunity for improved participation in prospective randomized trials designed to test the optimal management of node-positive prostate cancer.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Badrinath R. Konety, Daniel W. Lin) for the series “Current and Future Topics on Prostate Cancer” published in Translational Andrology and Urology. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at http://dx.doi.org/10.21037/tau-20-1031

Peer Review File: Available at http://dx.doi.org/10.21037/tau-20-1031

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tau-20-1031). The series “Management of Advanced Genitourinary Malignancies” was commissioned by the editorial office without any funding or sponsorship. Dr. RCC reports personal fees from Myovant, personal fees from Abbvie, personal fees from Accuray, personal fees from Blue Earth, outside the submitted work. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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