Apples and Oranges: The Evidence Regarding Lateral Pelvic Lymph Node Dissection for Rectal Cancer

In recent years, there has been a remarkable growth in interest regarding the clinical relevance of lateral pelvic lymph nodes (LPLN) for mid to low rectal cancers. The initial concept arises from Japan, where LPLN dissection (LPLND) was performed for T3–4 and/or N+ rectal cancer below the peritoneal reflection to address the risk of lateral pelvic lymph node metastasis which was observed to be as high as 23%.¹ In contrast, the treatment algorithm has differed in the West to include neoadjuvant pelvic radiation therapy for the management of extra-mesorectal disease in locally advanced rectal cancer.² In addition while the focus in the West has been predominantly on the quality of the mesorectal excision with the aim of decreasing central recurrences, the emphasis in the East has been on completeness of lymphadectomy. While the role of LPLND vs neoadjuvant radiation therapy continues to be debated, there is now a shift in thinking with growing recognition that for some patients, neither strategy alone is sufficient to provide optimal disease control.

In this issue of Surgery, Emile et al. (https://doi.org/10.1016/j.surg.2020.11.010) report a meta-analysis comparing the short-term surgical and intermediate-term oncological outcomes of LPLND and total mesorectal excision (TME) to TME alone for rectal cancer. The authors identified 29 studies, including 23 studies from Japanese centres. Four were reports of a single randomized trial without neoadjuvant therapy, one a small randomized trial after chemoradiotherapy, and one an ad hoc, non-randomized secondary analysis of a randomized trial of adjuvant chemotherapy without radiation. Twenty-two were retrospective studies with 7 reporting exclusively on patient cohorts treated prior to 2000. The authors compared operative complications, recurrence (local and distant), and survival (overall and disease free). Overall, they concluded that the addition of LPLND was associated with a higher rate of complications but no differences in recurrence or survival.

An important challenge for interpreting the literature regarding LPLND for rectal cancer is the heterogeneity of the patient groups. This challenge can be compounded when attempting to combine the data together in a meta-analysis. Some of important factors that need to be considered when interpreting the evidence include the intent of dissection, the use of neoadjuvant radiotherapy, the underlying clinical assessment of LPLN metastasis, and the decision to proceed with LPLND or not. For example, closer evaluation of studies reporting on therapeutic LPLND reveals that the decision for LPLND was based on selection of patients with high-risk disease who were compared to those with low-risk disease who did not undergo dissection. So, the fact that outcomes among those who underwent LPLND were not worse than those who did not undergo dissection may actually suggest a therapeutic benefit.

Furthermore, in this analysis, the majority of studies were from Japan where it has been routine for Japanese patients to undergo prophylactic LPLND in the absence of neoadjuvant therapy, which is in accordance to the Japanese Society for Cancer of the Colon and Rectum Guidelines.¹ In the only RCT (JCOG0212) on prophylactic LPLND for patients without radiological evidence of suspicious LPLN metastasis, a significantly higher rate of lateral pelvic recurrence occurred without LPLND: 7% in the TME plus prophylactic LPLND compared to 13% in the TME alone.³ But this study did not include preoperative radiotherapy which is the strategy used in the West for prophylactic indication.

To date there are no randomized control trials interrogating the oncological benefits of therapeutic LPLND after neoadjuvant chemoradiation for patients clinically suspected to have LPLN metastasis. In that regards, high-quality rectal protocol MRI has allowed clinicians to detect high risk features associated with the primary rectal cancer including suspicious lateral pelvic lymph nodes. This was critically examined in a multi-centered retrospective study which compared outcomes for those patients who had LPLN with a short axis of 7 mm or more on pre-treatment MRI and underwent neoadjuvant therapy with TME and with or without LPLND based on institutional policy. Those who underwent LPLND had a much lower LPLN recurrence after a therapeutic dissection, with a reported rate of 5.7% compared to 19.5% in the TME alone group.⁴ These data suggest neoadjuvant chemoradiation alone is not sufficient to reduce the risk of lateral pelvic recurrence. However, it has also been shown that LPLND without neoadjuvant therapy is also not sufficient for local control as evidence by an approximately 20% risk of local failure among patients identified to have LPLN metastasis at dissection without neoadjuvant radiotherapy.⁵

When interpreting retrospective studies of LPLND, either after neoadjuvant therapy or when therapeutic dissection was performed, the inclusion criteria and the comparison groups need to be scrutinized as differences in disease at presentation or post-treatment evaluation often drive the surgical decisions. When these factors between groups are controlled, local recurrence and recurrence-free survival has been shown to be improved by LPLND. In a recent study published after the inclusion window for this meta-analysis, oncological outcomes following therapeutic LPLND for persistently enlarged LPLN after neoadjuvant chemoradiotherapy were compared to those undergoing TME alone. Among patients with clinical evidence of LPLN metastasis, local control (local failure 5.4% vs 20.1%, p=0.001) and relapse-free survival (77.1% vs 65.8%, p=0.044) were improved with LPLND.⁶ Indeed post-treatment short-axis LN size ≥ 5 mm on MRI appears to be a sensitive criterion for establishing the indication for therapeutic LPLND.⁷

Over the past decade, considerations regarding the role of LPLND in rectal cancer have evolved. What used to be a simple debate between dissection in the East vs neoadjuvant therapy and no dissection in the West is now recognized to be clearly more nuanced. Whether dissection is performed with prophylactic intent or for the therapeutic management of LPLN metastasis and whether done with or without neoadjuvant radiotherapy are essential considerations. It is clear that there is an increased risk of lateral pelvic compartment failure in a subset of locally advanced rectal cancers that will benefit from both neoadjuvant therapy and LPLND but that not all patients require LPLND. Stratifying patients according to their risk profile based can allow clinicians to mitigate the morbidity associated of LPLND while optimizing oncologic benefit.