Importantly, the documented postoperative natural history of patients with lymph node positive disease at radical prostatectomy is relatively heterogeneous. In fact, up to 30% of patients with positive lymph nodes may remain free of disease long-term following surgery without further therapy.204-206 As such, assessment of the risk for subsequent disease progression among patients with positive lymph nodes is warranted to guide the judicious use of secondary therapy. Various clinicopathologic features have been associated with oncologic outcomes in this setting, particularly the number of positive nodes identified.207 Further, while salvage therapy would be appropriate for such patients with a persistently detectable PSA after radical prostatectomy, the Panel believes that patients with an undetectable PSA may be offered adjuvant treatment versus continued PSA surveillance. Of note, a randomized trial in 98 patients assessed the use of immediate, indefinite ADT after radical prostatectomy for patients with lymph node positive disease versus delayed treatment with ADT (largely at the time of systemic progression).193 At the median 11.9 year follow-up, immediate ADT was associated with improved PFS (HR 3.42, 95% CI 1.96 to 5.98), prostate cancer-specific survival (HR 4.09, 95% CI 1.76 to 9.49), and OS (HR 1.84, 95% CI 1.01 to 3.35). However, relevant to contemporary management, the trial did not assess the comparative outcomes of adjuvant ADT versus ADT initiated at the time of biochemical recurrence, thus the optimal timing to initiate postoperative ADT for patients with lymph node positive disease remains to be determined. Interestingly, six cohort studies investigating this topic have reported mixed findings.208-213 Three studies found no significant association between treatment with adjuvant ADT208, 210, 213 and oncologic outcomes including biochemical recurrence-free survival, metastasis-free survival, prostate cancer-specific survival, and OS, while three studies found improvement in various cancer-specific outcomes in certain populations.209, 211, 212 The role of postoperative radiation for patients with lymph node positive disease has not to date been addressed in the prospective clinical trial setting. Rather, a number of cohort studies have reviewed the outcomes of patients with lymph node positive disease treated with adjuvant ADT with or without adjuvant radiation as well.210-212, 214-218 Five of those studies demonstrated improvements in a variety of oncologic outcomes, including overall and cause-specific survival when adjuvant radiation therapy was added to ADT.210, 211, 214, 217, 218 In addition, a retrospective analysis noted superior metastases-free survival among patients with lymph node positive disease treated with adjuvant radiation versus a cohort who received no treatment/salvage radiation.210 Nevertheless, the absence of prospective data preclude definitive recommendations regarding the optimal timing of radiation in patients with lymph node involvement at surgery. Therefore, the Panel believes that both adjuvant therapies (e.g., ADT, radiation) as well as surveillance with the option for early salvage therapy should the patient experience PSA relapse may be utilized for patients with positive lymph nodes at radical prostatectomy and an undetectable postoperative PSA. The approach taken should be based on SDM, including an assessment of disease risk stratification (e.g., number of positive nodes, primary tumor features) as well as the potential toxicities of additional therapies.