Lymph node‐positive prostate cancer—From middle child to the new frontier

Men diagnosed with lymph node-positive prostate cancer (N1M0) are classified to have stage IV disease, the same stage as men with distant metastatic (M1) disease. This may reflect a traditional, pessimistic view on the prognoses of these patients. There was a time not too long ago when, during surgery for a patient with high-risk prostate cancer, some urologists might sample pelvic lymph nodes first and, if the results were positive, then radical prostatectomy was aborted. Furthermore, historically, patients with lymph node-positive disease have been largely ignored by clinical trial investigators. Although numerous clinical trials have been conducted to help establish and continue to refine the standard of care for patients with localized disease (low risk, intermediate risk, and high risk) and for those with metastatic (M1) prostate cancer, lymph node-positive disease has been treated like the middle child—perhaps not advanced enough to get the interest of pharmaceutical companies to test new systemic agents, but not localized enough for testing of curative-intent treatment regimens. One of the very few trials conducted for patients with lymph node-positive disease was Eastern Cooperative Oncology Group trial 3886, led by Dr. Messing. Among 98 patients who had pathologic lymph node-positive disease identified on radical prostatectomy who were randomized to no further treatment versus lifelong androgen-deprivation therapy (ADT), the latter improved overall survival. That result provides the only level 1 evidence for these patients and supports the use of lifelong ADT, although it is not clear that most practicing urologists or medical oncologists actually adopt this long-term treatment. Consequently, the optimal management of patients with lymph node-positive prostate cancer is largely undefined. There are 2 categories of lymph node-positive patients—those with clinically lymph node-positive disease (identified on staging computed tomography or magnetic resonance imaging scans), and those with pathologically lymph node-positive disease (positive lymph nodes identified in the radical prostatectomy specimen). For the former patients, published guideline recommendations range from ADT alone (a palliative approach) to definitive treatment. For the latter patients, recommendations range from observation, to adjuvant ADT alone, to ADT plus radiotherapy. These options are as wideranging as could be, and they reflect the current knowledge gap for these patients and a need for research to help define the optimal management. Several factors are helping to move lymph node-positive disease from the middle child to the new frontier in prostate cancer. First, this group represents a sizable proportion of all men diagnosed with prostate cancer (12%), and this is likely to continue to increase with less prostate-specific antigen screening. This means that clinical trials to define the optimal management will benefit a sizable number of patients. Of note, the discussions regarding over-treatment of prostate cancer do not apply to those patients who have cancers that already have a proven ability to metastasize. Second, improvements in systemic therapy provide the hope of a cure for patients who historically were considered to have a poor prognosis. This has been observed in multiple other cancers, and such improvements in systemic therapy make local treatment even more relevant and important and can be applied to prostate cancer as well. If effective systemic agents can cure micrometastatic disease, then their combination with aggressive local treatments may offer more patients the possibility for cure. With increasing recognition that active surveillance is a preferred option for patients with low-risk prostate cancer and that many patients with early diagnoses do not need immediate treatment, the other end of the spectrum—patients with aggressive cancers—is the next frontier for prostate cancer research. There is increasing interest in studying whether aggressive treatments for some patients with stage IV disease (lymph node-positive prostate cancer and even oligometastatic disease) lead to improved survival.