Management of Men With Lymph Node Metastases Following Radical Prostatectomy: What Is the Optimal Treatment Strategy?

NYU Case of the Month, March 2020

Case of the Month Management of Men With Lymph Node Metastases Following Radical Prostatectomy: What Is the Optimal Treatment Strategy? NYU Case of the Month, March 2020 Mohit Gupta, MD NYU Grossman School of Medicine, New York, NY; Director of Urological Oncology, NYU Langone Hospital— Brooklyn, Brooklyn, NY [Rev Urol. 2020;22(1):37–39] © 2020 MedReviews®, LLC A 55-year-old healthy man was referred for management of unfavorable intermediaterisk prostate cancer. Initial prostate cancer screening by his primary care physician had shown an elevated prostate-specific antigen (PSA) of 11.2 ng/mL (free PSA 14%). Systematic transrectal ultrasound-guided biopsy by his local urologist had demonstrated Gleason 4+3=7 (Gleason Grade Group 3) in 7 of 12 cores and Gleason 3+4=7 (Gleason Grade Group 2) in 2 of 12 cores. Digital rectal examination revealed a left base 1-cm nodule with no extracapsular extension. The patient’s Sexual Health Inventory for Men (SHIM) score was 25 and his International Prostate Symptom Score (IPSS) was 1. He had no family history notable for prostate cancer. He had no significant medical comorbidities and his performance status was excellent. Given the patient’s National Cancer Comprehensive Network (NCCN) unfavorable intermediate-risk biopsy findings, staging nuclear medicine bone scan and CT of the abdomen and pelvis were obtained; these were negative for evidence of pelvic lymphadenopathy as well as for visceral and osseous metastatic disease. Management The patient was counseled on his management options and elected to undergo robot-assisted radical prostatectomy (RP) with bilateral extended pelvic lymph node dissection. Surgical pathology revealed high-volume Gleason 4+4 (Gleason Grade Group 4) cancer, occupying 65% of the gland, with bladder neck invasion. The final stage was pT3a, N1 (3 of 18 nodes positive), Mx, with a positive bladder neck margin. Following surgery, the first postoperative PSA value was 0.05 ng/dL. Given the presence of node-positive disease, the patient was referred to Radiation Oncology and completed adjuvant radiation therapy with 24 months of androgen deprivation therapy (ADT). In follow-up, the patient’s PSA level was <0.01 ng/dL and remained undetectable at 3 years following radiation therapy. Comment Through the rise of PSA screening and earlier detection of prostate cancer, the incidence of lymph node metastases (LNM; pN1) following RP has decreased. The presence of LNM, however, is still 4% to 9% in Vol. 22 No. 1 • 2020 • Reviews in Urology • 37 4170020_10_RIU0870C_V1_rev02.indd 37 5/12/20 9:34 PM Lymph Node Metastases Following RP continued the PSA era.1 And given the recent shift of surgical focus to high-risk, localized prostate cancer and the decreased use of PSA screening following contentious guideline debates, there is a concern that node-positive prostate cancer after RP may become a more prevalent clinical entity in coming years.2-4 The optimal management strategy for men with LNM following RP, however, remains undefined. Although there is extensive literature addressing the management of localized and metastatic prostate cancer, prospective data to help guide treatment for patients with LNM after RP are lacking, and most patients are managed according to their physician’s preferences or institutional practice patterns.5 Current management options include adjuvant ADT, multimodal adjuvant therapy with ADT and external beam radiation therapy (EBRT), or observation followed by salvage treatment in the case of biochemical recurrence. It is unclear, however, whether either adjuvant treatment strategy provides a durable oncological benefit over the other or in comparison to observation alone, and the optimal time and duration of hormone therapy also continue to be debated.6-8 The seminal trial by Messing and colleagues is the only randomized trial with level 1 evidence evaluating patients with LNM disease after RP (treatment period 1988-1993).9 The trial randomized 98 men with pN+ prostate cancer to immediate ADT or observation and, after 11.9 years of follow-up, found immediate ADT significantly improved overall survival (hazard ratio [HR] 1.84; 95% CI, 1.01-3.35; P = 0.04). Notably, however, because of the pre-PSA era study design, ADT was not used in the observation arm until there was evidence of metastatic or symptomatic disease progression, not biochemical recurrence. Given the small sample size of the trial and the poor survival outcomes of the observation group—randomized nearly 25 years ago—the trial’s findings may not be applicable in the modern PSA era. Other studies evaluating the use of ADT with radiation therapy did not have observational arms, document use/duration of ADT, or adequately evaluate prognostic features to determine which patients would benefit from adjuvant therapy.10-13 Thus, limited prospective data exist to guide optimal treatment strategies for patients with LNM. In the absence of contemporary randomized trials, recent retrospective studies have provided several key insights into the management of LNM following RP. Although node-positive prostate cancer has conventionally been thought of as a systemic disease— the American Joint Committee on Cancer staging criteria classify patients with node-positive disease in the same stage grouping as patients with distant metastatic disease—recent evidence suggests that patients with node-positive disease represent a heterogeneous population.14,15 Indeed, long-term data on men observed after RP alone have shown 10-year progression-free survival rates of nearly 65% and freedom from biochemical recurrence rates of nearly 30%.16,17 These data show that not all patients found with LNM following RP share the same long-term poor prognosis as all patients with stage IV prostate cancer. Additional recent studies have also found that survival outcomes in patients with LNM are not uniform but instead depend on multiple pathological factors, including lymph node burden, Gleason score, and positive margin status.18 In fact, patients with a low volume of LNM have been found to have significantly higher rates of cancerspecific survival (CSS) and recurrence-free survival (RFS) compared with patients with more extensive nodal burdens.15,19,20 Boorjian and colleagues, for example, found that the risk of prostate cancer death in patients with 2 or more positive lymph nodes was increased twofold compared with the risk in patients with 1 positive node (HR 2.2; 95% CI, 1.3-3.5; P = 0.001).18 Similarly, Daneshmand and colleagues reported clinical RFS rates above 70% in men with 1 or 2 positive lymph nodes at 10 years.19 By contrast, the authors found clinical RFS rates of 49% with 5 or more positive nodes at 10 years. As a result, select pN1 patients may arguably be managed with observation alone and spared the comorbidities associated with adjuvant therapy and the risk of overtreatment. Taken together, these findings demonstrate the importance of substratification of patients with node-positive disease. Indeed, recent studies have evaluated prognostic features to identify which men would derive the greatest benefit from therapy and which men can be observed. Touijer and colleagues retrospectively evaluated the use of observation, ADT, and ADT with EBRT in 1338 patients with LNM treated at three tertiary care centers.21 Study findings indicated that ADT with EBRT improved survival in patients compared with either observation or adjuvant ADT alone and that the survival benefit increased in patients with higher-risk disease. A study using the National Cancer Database found that use of ADT with EBRT improved overall survival versus observation (HR 0.77; 95% CI, 0.64–0.94; P = 0.008) and versus ADT alone (HR 0.76; 95% CI, 0.63–0.93; P = 0.007).5 This benefit was present only in patients with 1 or more adverse 38 • Vol. 22 No. 1 • 2020 • Reviews in Urology 4170020_10_RIU0870C_V1_rev02.indd 38 5/12/20 9:34 PM Lymph Node Metastases Following RP pathological features: ≥pT3b disease, Gleason score ≥9, 3 or more positive nodes, or positive surgical margins. Conversely, there was no difference in survival, regardless of treatment type, in nearly 30% of patients who lacked any these adverse features; the authors posited that patients without these high-risk factors could be managed with observation until they developed evidence of biochemical recurrence. Indeed, both studies found that patients with the most adverse pathological features demonstrated the greatest benefit from adjuvant ADT with EBRT. These retrospective studies suggest that although initial observation might be a valid option for lymph node–positive patients with less aggressive disease characteristics, use of adjuvant ADT with EBRT may confer a survival benefit on men with aggressive pathological features. Thus, patients with LNM should be stratified and may consequently be better managed by withholding treatment until they develop evidence of biochemical recurrence in order to avoid treatment-related side effects and preserve quality of life.5 Ultimately, randomized trials will be required to establish the true benefit of adjuvant treatment compared with observation and the optimal treatment paradigm for patients with LNM following RP. Use of genomic classifiers will likely also need to be evaluated to determine their role in helping physicians select patients who would benefit from adjuvant treatment. Prospective information on the benefits of adjuvant versus salvage treatment pursued at the time of disease recurrence is also needed. 8. 9. 10. Conclusions Patients with LNM following RP are a heterogeneous population. Recent retrospective studies suggest that adjuvant treatment with ADT with EBRT may confer a survival benefit on patients with adverse pathological features. Conversely, men without high-risk features on pathology may be managed initially with observation alone. Prospective, randomized studies are needed to confirm these findings. 11. 12. 13. 14. 15. References 1. 2. 3. 4. 5. 6. 7. Palapattu GS, Allaf ME, Trock BJ, et al. Prostate specific antigen progression in men with lymph node metastases following radical prostatectomy: results of long-term followup. J Urol. 2004;172:1860–1864. Silberstein JL, Vickers AJ, Power NE, et al. Reverse stage shift at a tertiary care center: escalating risk in men undergoing radical prostatectomy. Cancer. 2011;117:4855–4860. 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