Elective nodal radiotherapy (ENRT) is a commonly used strategy to eradicate micro-metastatic disease in the regional nodes, and it has shown to improve locoregional disease control for several cancer sites, such as head-neck, breast, rectal, and cervical cancers. However, it has not been shown to improve disease outcomes for certain sites, such as lung and esophageal cancers. For prostate cancers, this has been a subject of long-standing controversy.1 So far, none of the randomized trials addressing this question have shown improvement in overall survival with ENRT compared to prostate-only radiation. These trials have also shown some increase in mild to moderate gastrointestinal (GI), genitourinary (GU) toxicities, or hematologic toxicities. However, the proponents of ENRT believe that the lack of benefit is probably due to the improper patient selection, suboptimal radiation dose, and volumes used in these trials; and newer radiation techniques can possibly mitigate the ENRT-related additional toxicities. This controversy extends to the postoperative setting, both in the adjuvant and the salvage setting after biochemical recurrence.

The controversy has led to a wide variation in ENRT use globally. Even among the advocates of ENRT, there is variation in the method of patient selection, dose, volumes, radiation techniques, type, and duration of androgen deprivation therapy (ADT); all of the factors that can potentially influence the benefit of ENRT. This strategy continues to evolve with an improved understanding of regional spread and patterns of failure with contemporary imaging techniques such as PSMA PET-CT scans and a better understanding of adverse pathological factors, including molecular and genetic scores. The renewed enthusiasm for understanding the benefit of ENRT is due to recent publications in this space as well as ongoing prospective studies addressing this issue. For ENRT to improve clinical outcomes, the following criteria may be important: patients with a sufficiently high risk of nodal disease and yet negative on imaging, ENRT volumes encompassing all or most of the potential nodal disease, use of appropriate radiation technique, dose/fractionation and optimal ADT duration that enables adequate disease control with acceptable toxicities.

This article aims to review the existing literature and ongoing trials on ENRT both in the definitive and post-prostatectomy settings. It will also provide guidance for practicing radiation oncologists on the nuances of patient selection, radiation techniques, target delineation, dose and fractionation schedules adopted when using this approach.

Our understanding of lymphatic drainage of the prostate gland has largely been derived from the data from lymphangiography series, surgical series and data from imaging, including contemporary techniques such as PSMA PET scans. Prostate lymphangiography data suggests that lymphatic drainage from the superolateral angle of the prostate courses along the lateral pelvic wall to drain into the internal iliac lymph nodes.2 Lymphatic drainage from the posterior portion of the gland moves to the base of the gland which drains into hypogastric nodes and ends in presacral and sacral promontory nodes. Lymphatics from the anterior portion of the gland descend toward the prostate apex draining into those along the internal pudendal artery and internal iliac lymph nodes. Additional spread is to the perirectal and lower sacral nodes, proximal external iliac, obturator, upper sacral, common iliac, and, ultimately, para-aortic lymph nodes and beyond.

Mattei et al.3 used Technetium-99m-labeled nanocolloid, single-photon emission CT, MRI, and super-extended pelvic lymph node dissection (PLND) to show that extended PLND (external iliac, obturator, and internal iliac) clears only 63% of prostatic nodal drainage. In 18% of patients, sentinel nodes were located in the common iliac region, prompting recommendations to include these nodes in surgical and ENRT templates. Joniau et al.4 similarly advocated for presacral node inclusion. These findings have informed and helped in evolving contouring guidelines, which have been discussed later.

PSMA PET scans have further refined our understanding. PSMA-PET has shown high specificity (Sp) and positive predictive value (PPV) for detecting pelvic lymph nodes in intermediate (Sp 96%, PPV 93%) and high-risk patients (Sp 93%, PPV 86%), with relatively low sensitivity(40%-58%).5 This implies that the absence of nodal disease on PSMA PET does not rule out microscopic involvement of pelvic lymph nodes, and the presence of nodal involvement can reliably identify patients for treatment intensification (either local or systemic). PSMA PET also enables the prediction of atypical patterns of nodal spread6 that may influence the treatment volumes and outcomes. For example, metastases to mesorectal nodes are relatively more prevalent (approximately 15%) than believed.