For decades, lymph node metastasis (LNM) at the time of radical prostatectomy (RP) has been considered as a poor prognostic sign. Currently, the appropriate timing for androgen deprivation therapy (ADT) remains controversial. Only one small prospective randomized study (ECOG 3886) has shown improved survival for immediate vs. delayed ADT in this select group of patients (1). However, given that most urologists will not delay hormone therapy for evidence of bulky metastatic disease as was done in that trial, the study’s findings do not apply to the contemporary management of biochemically recurrent (BCR) prostate cancer. In today’s PSA era, immediate ADT would lead to overtreatment for a significant number of patients along with its associated risks and adverse effects (2,3).
The presence of LNM, or pN+ disease, has traditionally been seen as a sign of disseminated disease with lymphadenectomy playing more of a staging rather than therapeutic role. However, emerging evidence has provided insight into this complex issue; with longitudinal data demonstrating a considerable subset of men can be free of disease at 10 years with lymphadenectomy alone (4). Patients with low Gleason score and low number of metastatic lymph nodes appear to be a favorable group for whom an extended pelvic lymph node dissection (PLND) may be beneficial (5,6). The need and timing of adjuvant treatments remains less clear with current national comprehensive guidelines labeling ADT and ADT plus pelvic radiotherapy (RT) as a category 1 and 2B, respectively (7). Only one retrospective report from the Vita-Salute San Raffaele University (Milan, Italy) demonstrated improved BCR-free and cancer specific survival for men treated with ADT plus RT vs. ADT alone after RP and PLND (8).
This same center partnered with the Mayo Clinic and Memorial Sloan-Kettering Cancer Center in the latest issue of European Urology examining long term outcomes between different management strategies for pN+ men (9). Based on practice patterns at each institution, their large cohort of 1,388 men was comprised of three arms: observation (28%), ADT (49%), and ADT + RT (23%). Of note was their median follow-up of 69 months with 368 (26%) men followed longer than 10 years. Their results showed ADT + RT was associated with better overall survival than ADT [hazard ratio (HR): 0.46, 95% CI: 0.32–0.66; P<0.01] or observation alone (HR: 0.41, 0.27–0.64; P<0.01). This benefit seemed greater for those with high-risk disease features such as high Gleason score, pathologic T3b/T4 stage, and positive surgical margin; which correspond with previously reported data that also included Milan and Mayo Clinic patients (10).
Interestingly, there were no differences in survival between ADT and observation alone; with lifelong adjuvant ADT associated with increased risk of death from other causes (HR: 3.05, 1.45–6.40; P=0.003). However, it is noteworthy that approximately 77% of patients in the ADT arm came from US centers which tracked deaths using the Social Security Death Index (as opposed to the Italian National Civil Registry) so these results may be affected by spurious differences in coding between the two registries. Additionally, most of the ADT + RT patients (83%) came from Milan so these findings may not necessarily translate to North American cohorts with distinct lifestyle, medical, and environmental factors which can confound retrospective studies such as this one. Nevertheless, the authors are to be congratulated for providing the largest experience to date on the post-operative management of pN+ disease after RP and PLND. These findings add to the evidence for the benefit of surgical resection and local control for a complex and heterogeneous disease state in which prospective data is unlikely to be forthcoming given the downward stage migration caused by widespread PSA screening (11,12).
Selecting patients who would benefit from adjuvant treatments remains difficult. What is clearer, as data continues to show, is the dogma that pelvic LMN is invariably a ‘game-over’ for prostate cancer patients. Even those with ominous pathologic features may derive benefit from aggressive local consolidation, and referral to centers of experience with multidisciplinary management of high-risk prostate cancer should be considered. With advances in systemic therapy targeting the androgen receptor, there is also an opportunity to improve hormonal manipulation and assess oncologic benefit in both adjuvant and salvage settings. What remains to be better defined is the subset of patients who may not require or benefit from adjuvant therapies, thus also sparing them the adverse consequences of castration and radiation effects on quality of life. Additionally, there is an opportunity to evaluate novel molecular biomarkers which could allow for better risk stratification with the goals of maximizing oncologic benefit while minimizing morbidity of overtreatment.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Messing EM, Manola J, Yao J, et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 2006;7:472-9. [Crossref] [PubMed]
- Crawford ED, Moul JW. ADT risks and side effects in advanced prostate cancer: cardiovascular and acute renal injury. Oncology (Williston Park) 2015;29:55-8, 65-6. [PubMed]
- Nguyen PL, Alibhai SM, Basaria S, et al. Adverse effects of androgen deprivation therapy and strategies to mitigate them. Eur Urol 2015;67:825-36. [Crossref] [PubMed]
- Touijer KA, Mazzola CR, Sjoberg DD, et al. Long-term outcomes of patients with lymph node metastasis treated with radical prostatectomy without adjuvant androgen-deprivation therapy. Eur Urol 2014;65:20-5. [Crossref] [PubMed]
- Carlsson SV, Tafe LJ, Chade DC, et al. Pathological features of lymph node metastasis for predicting biochemical recurrence after radical prostatectomy for prostate cancer. J Urol 2013;189:1314-8. [Crossref] [PubMed]
- von Bodman C, Godoy G, Chade DC, et al. Predicting biochemical recurrence-free survival for patients with positive pelvic lymph nodes at radical prostatectomy. J Urol 2010;184:143-8. [Crossref] [PubMed]
- Mohler JL, Kantoff PW, Armstrong AJ, et al. Prostate cancer, version 2.2014. J Natl Compr Canc Netw 2014;12:686-718. [Crossref] [PubMed]
- Da Pozzo LF, Cozzarini C, Briganti A, et al. Long-term follow-up of patients with prostate cancer and nodal metastases treated by pelvic lymphadenectomy and radical prostatectomy: the positive impact of adjuvant radiotherapy. Eur Urol 2009;55:1003-11. [Crossref] [PubMed]
- Touijer KA, Karnes RJ, Passoni N, et al. Survival Outcomes of Men with Lymph Node-positive Prostate Cancer After Radical Prostatectomy: A Comparative Analysis of Different Postoperative Management Strategies. Eur Urol 2017. [Epub ahead of print]. [Crossref] [PubMed]
- Abdollah F, Karnes RJ, Suardi N, et al. Impact of adjuvant radiotherapy on survival of patients with node-positive prostate cancer. J Clin Oncol 2014;32:3939-47. [Crossref] [PubMed]
- Cooperberg MR, Lubeck DP, Mehta SS, et al. Time trends in clinical risk stratification for prostate cancer: implications for outcomes (data from CaPSURE). J Urol 2003;170:S21-5; discussion S26-7.
- Galper SL, Chen MH, Catalona WJ, et al. Evidence to support a continued stage migration and decrease in prostate cancer specific mortality. J Urol 2006;175:907-12. [Crossref] [PubMed]