Current Status and Future Perspective on the Management of Lymph Node-Positive Prostate Cancer after Radical Prostatectomy

Simple Summary pN1 after RP with PLND represents one of the most unfavorable prognostic factors for disease recurrence and cancer-specific mortality in prostate cancer. Treatment intensification may reduce risks of recurrence and cancer-specific mortality, but it may increase adverse events and impair quality of life. However, optimal management for pN1 patients remains unclear. Nevertheless, few randomized control trials for pN1 are under investigation, and then more research is needed to establish an optimal therapeutic strategy for patients with pN1. This review summarizes current evidence on the treatments available for men with pN1, summarizes RCTs that included pN1 prostate cancer, and also discusses future perspectives. Abstract Pathological lymph node involvement (pN1) after a pelvic lymph node dissection represents one of the most unfavorable prognostic factors for disease recurrence and cancer-specific mortality in prostate cancer. However, optimal management for pN1 patients remains unclear. Thus, the guideline from the European Association of Urology recommends discussing three following management options with pN1 patients after an extended pelvic lymph node dissection, based on nodal involvement characteristics: (i) offer adjuvant androgen-deprivation therapy, (ii) offer adjuvant androgen-deprivation therapy with additional radiotherapy and (iii) offer observation (expectant management) to a patient with ≤2 nodes and a prostate-specific antigen <0.1 ng/mL. Treatment intensification may reduce risks of recurrence and cancer-specific mortality, but it may increase adverse events and impair quality of life. Few randomized control trials for pN1 are under investigation. In addition, there are limited reports on the quality of life and patient-reported outcomes in patients with pN1. Therefore, more research is needed to establish an optimal therapeutic strategy for patients with pN1. This review summarizes current evidence on the treatments available for men with pN1, summarizes randomized control trials that included pN1 prostate cancer, and discusses future perspectives.


Introduction
Pelvic lymph node dissection (PLND) is recommended during radical prostatectomy (RP) for prostate cancer in clinical practice, depending on risk classification [1]. PLND is the gold standard procedure for the diagnosis of lymph node involvement (LNI), although so far, its therapeutic value has not been proven [2,3]. Pathological LNI (pN1) rates after RP with PLND vary between 0% and 37% depending on risk classification and the areas removed in PLND [4]. LNI represents one of the most unfavorable prognostic factors for recurrence and cancer-specific mortality [5].
So far, the only randomized clinical trial (RCT) performed for patients solely with pN1 prostate cancer showed that immediate androgen deprivation therapy (ADT) was

The Prognosis in pN1 Prostate Cancer by Treatments
Several retrospective studies reported the prognosis in pN1 prostate cancer (Table 1). Since the standard treatment for pN1 has not been established, management strategies differed among studies. Biochemical recurrence (BCR)-free survival rate is affected by adjuvant therapy and varies from 28% to 61% at five years. Recurrence-free survival (RFS), determined basically by radiological recurrence, and metastasis-free survival (MFS) was 55-84% and 65-80% at 10 years, respectively. Cancer-specific survival (CSS) and OS werẽ 80% and~70% at 10 years, respectively. Although survival in patients with pathological negative LNI (pN0) or unknown LNI (pNx) after RP is generally excellent, the prognosis in pN1 prostate cancer is inferior, making the improvement of treatment outcomes an unmet need, where treatment intensification is an attractive approach.  Interestingly, Moschini et al. have reported the natural history of clinical recurrence patterns of pN1 prostate cancer using a database from the Mayo Clinic, where almost all patients received adjuvant or salvage ADT, and 22% received adjuvant or salvage RT [9]. In that study, 17% and 28% of patients presented clinical recurrence in soft local tissues and pelvic lymph nodes, respectively [9]. Similarly, prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) detected positive lesions only in the pelvic area in 65%, only outside the pelvic area in 10%, and both in 25% of patients [22]. Those findings on the locations of recurrent disease in pN1 prostate cancer suggest that loco-regional disease control after RP is feasible in a subset of patients. Table 2 shows retrospective studies and database studies on the prognostic differences with the addition of RT. Tilki et al. and Da Pozzo et al. have reported favorable BCR-free survival and MFS with adjuvant RT than those men without adjuvant RT, using large case series from a European institution [10,23]. Similarly, it has recently been reported that RT for persistent PSA after RP was associated with improved RFS and MFS in large case series from Japanese multiple institutions [19]. Consistently, several retrospective studies from high-volume centers in the United States (US) and Europe have reported that RT plus adjuvant ADT was associated with better CSS and OS [15,16,23,24]. Similarly, other studies using a national database in the US have demonstrated that patients treated with adjuvant RT were associated with better CSS and OS than those without adjuvant RT [25][26][27][28]. Thus, the addition of RT to immediate ADT may result in favorable disease control and better survival. However, careful interpretation is necessary because retrospective studies suffer from potential biases, such as treatment selection. Thus, it is necessary to examine the value of RT for pN1 prostate cancer in RCTs.  Treatment de-intensification is another approach for pN1 patients with a favorable prognosis. Tilki et al. had demonstrated that BCR-free survival and MFS were better in men who received adjuvant RT compared with no treatment or salvage RT using large case series data from Martini-Klinik [10]. Moreover, they have recently reported a higher CSS with adjuvant RT than with salvage RT [30]. Consistently, expectant management for pN1 was associated with inferior survival than adjuvant treatment including RT in retrospective case series and database studies [24,27,28,31]. In contrast, the RADICALS-RT trial that enrolled mainly pN0 or pNx in addition to pN1 patients has recently reported a comparable BCR rate between adjuvant RT and salvage RT [32]. However, this RCT included only 5% of patients with pN1, limiting the applicability of the findings [32]. Based on these studies, the EAU guideline recommends observation in limited patients with favorable prognosis features [1]. Thus, stratification by patient's and tumor's characteristics may be a promising approach.

Treatment Burden in pN1 Patients
RP with PLND could cause various postoperative complications such as urinary incontinence, erectile dysfunction, bladder neck contracture, and inguinal hernia, reducing the quality of life (QoL). The Prostate Testing for Cancer and Treatment (ProtecT) trial, which randomized patients to receive monitoring, RP or RT, found the most significant negative effect on urinary continence and sexual function in those patients undergoing RP [33]. Similarly, a prospective trial showed that patients who underwent RP had worse urinary incontinence and a worse sexual domain score compared with patients with RT or active surveillance [34]. Thus, additional treatment after RP may lead to further deterioration in QoL.
Additionally, ADT can cause several adverse effects (AEs) including sexual dysfunction, hot flushes, bone fractures, metabolic effects, cardiovascular morbidity, fatigue, and neurological disorders [35]. A prospective observational study that included patients with locally advanced prostate cancer or PSA relapse after local therapy found that immediate ADT was associated with a lower overall QoL than in those with deferred treatment [36]. Consistently, in another prospective observational study, patients undergoing ADT, after RP or RT, showed higher levels of depression, worse self-body image perception, worse sleep quality, and worse QoL than controls [37].
Similarly, salvage RT is also associated with toxicity. A prospective study evaluating salvage RT plus ADT after RP showed increased bowel dysfunction and urinary dysfunction by the end of RT. These rates improved after RT completion, but not completely. Meanwhile, erectile function presented no change during RT but showed an abrupt decline after RP [38]. Similarly, in an observational study from the Martini-Klinik Prostate Cancer Center, patients who received RT after RP had a higher incontinence rate and lower potency rate than matched RP-only patients. Both rates increased further with the addition of ADT [39]. Thus, currently available data on toxicity demonstrate an increased incidence of acute and long-term grade 2 AEs and transient decline in QoL outcomes, but no significant increase in long-term grade 3-4 AEs with the use of RT after RP [40].
Based on this evidence, treatment addition after RP may lead to increased toxicity and reduced QoL. Meanwhile, treatment addition may reduce or delay recurrence, which may lead to a recovery of QoL by avoiding continuous ADT. However, there is little data on QoL and outcomes reported by patients with pN1. Thus, a prospective study on treatment strategies would be necessary.

RCTs That Include pN1 Prostate Cancer
So far, various RCTs have been conducted to develop adjuvant therapy for high risk of recurrence and salvage therapy for BCR after RP. Due to the unfavorable prognosis among men with pN1 prostate cancer, the development of novel treatment to suppress recurrence and improve survival is necessary. However, the frequency of pN1 prostate cancer is low, and so far, only the RCT by Messing et al. enrolled patients with pN1 only [6]. Moreover, a few RCTs included pN1 patients in addition to pN0 or pNx (Table 3). Among them, TAX3501 (NCT00283062) and TAX3503 (NCT00514917) trials examined the efficacy of docetaxel plus ADT after RP regardless of LNI in adjuvant or salvage setting. However, these RCTs showed no significant improvement in biochemical or radiographic progressionfree survival [41,42]. Similarly, the SWOG S9921 (NCT00004124) trial demonstrated no benefit in CSS and OS with the addition of mitoxantrone [17]. Meanwhile, the GETUG-AFU 12 trial included patients with high-risk nonmetastatic prostate cancer (stage T3-T4 disease, Gleason score of ≥8, PSA >20 ng/mL, or pN1) who underwent staging PLND without RP showed longer relapse-free survival with ADT plus docetaxel and estramustine than with ADT alone [43]. However, as patients included in this trial never underwent RP, it is not appropriate to apply this finding to patients with pN1 after RP and PLND.
To date (31 March 2022), several RCTs recruiting patients with pN1 are being performed (Table 4). Among them, two RCTs are recruiting patients solely with pN1. The INNOVATE NRG-GU008 (NCT04134260) trial is recruiting 586 patients with pN1 prostate cancer after RP, to evaluate the effect of apalutamide for two years on MFS and ADT plus RT to pelvis and prostate bed in an adjuvant setting. This RCT may expand the indication of a novel androgen receptor pathway inhibitor, apalutamide, to pN1 disease in case of a positive result. The PROPER (NCT02745587) trial is also recruiting solely pN1 patients. This trial compares the presence of clinical relapse (loco-regional recurrence or distant metastases) between RT to the prostate bed alone or in combination with the pelvic lymph node regions, plus two years of ADT in an adjuvant setting. The result of this RCT will be important to determine the appropriate field of RT for pN1 patients.
Moreover, six RCTs recruiting pN1 in addition to pN0 or pNx are under investigation (Table 3). However, these RCTs do not aim to develop the treatment specific for pN1. Actually, the reported standard treatments for pN1 patients are different across trials, making the generalization of results difficult.
In the future, ongoing RCTs may change the current therapeutic landscape in pN1 prostate cancer. As examined in the PATRON (NCT04557501) trial, PSMA PET/CT is a promising modality that has the potential to change the landscape of treatment strategies for prostate cancer. Recently, proPSMA Study Group Collaborators have reported that PSMA PET/CT showed higher accuracy for pelvic nodal metastases and distant metastases than traditional imaging modalities [44]. Despite excellent specificity, PSMA PET/CT presents a lower sensitivity (of~40%) for detection of positive pelvic lymph nodes than extended PLND [45][46][47]. This suggests that PSMA PET/CT alone cannot yet replace the diagnostic role of extended PLND, although combination with nomograms was suggested to improve predictive ability [48]. Meanwhile, PSMA PET/CT has shown good potential in patients with BCR after RP, where detection rates increase according to PSA level: 33% (95% confidence interval (CI), 16-51%) in PSA < 0.2 ng/mL, 45% (95% CI, 39-52%) in PSA 0.2-0.49 ng/mL, 59% (95% CI, 50-68%) in PSA 0.5-0.99 ng/mL, 75% (CI: 66-84%) in PSA 1.0-1.99 ng/mL, and 95% (95% CI, 92-97%) in PSA ≥2.0 ng/mL [49]. Thus, PSMA PET/CT may be useful for patients with BCR. However, the residual tumor is not detectable in most patients without BCR after RP, and a conventional therapeutic approach is necessary for those patients with no visible lesion. In addition, it is unknown whether a more sensitive diagnosis by PSMA PET/CT leads to improved outcomes, which will be addressed by the PATRON trial.  PSA, prostate-specific antigen; RP, radical prostatectomy; RT, radiotherapy; SOC, standard of care. † >10 ng/mL or PSA-doubling time < 12 months and PSA > 0.5 ng/mL after RP, and PSA > +2.0 ng/mL above nadir and PSA > 10 ng/mL or PSA-doubling time < 12 months and PSA > 0.5 ng/mL after RT. ‡ >1.0 ng/mL after RP and >2.0 ng/mL above nadir after RT.

Conclusions
In conclusion, pN1 represents an unfavorable characteristic in patients who underwent RP with PLND. Currently, a gold standard strategy for pN1 has not been established, and survival of patients with pN1 is not satisfactory. Thus, the development of novel treatments with more efficacy and less toxicity is an unmet need. Treatment intensification by adding novel antiandrogen as well as treatment guided by next-generation imaging are currently under investigation, and may become a standard of care in the future. However, a few RCTs are underway. In addition, as studies on QoL and patient-reported outcomes in patients with pN1 are scarce, more research on QoL and patient-reported outcomes is needed to develop a better therapeutic strategy for pN1 patients.