Management of Lateral Lymph Node Metastasis in Rectal Cancer

Abstract

Introduction: Pre-treatment abnormal lateral lymph nodes (LLNs) are present in approximately 20% of patients with locally advanced rectal cancer. Western treatment of LLNs consists of neoadjuvant (chemo)radiotherapy (nCRT) followed by total mesorectal excision (TME), meaning these nodes are not removed surgically. There is, however, potential benefit in performing an additional lateral lymph node dissection (LLND) as enlarged LLNs have been shown to be predictive for local recurrence. Furthermore, the impact on oncological outcomes when enlarged LLNs harbour malignant features is currently unknown. Therefore, the aims of this thesis were to investigate if patients benefit from an additional LLND after nCRT and to determine oncological outcomes when malignant features are present in enlarged LLNs. Methods: A multi-centre cohort study was conducted at six tertiary referral centres in the US, the Netherlands and Australia. All patients had locally advanced rectal cancer with enlarged LLNs with a short-axis of ≥5mm. Malignant features were defined as nodes with internal heterogeneity and/or border irregularity. Firstly, patients who underwent nCRT followed by TME (LLND-) were compared to those who underwent a LLND in addition to nCRT and TME (LLND+). Next, a systematic review and meta-analysis was performed on studies comparing LLND- versus LLND+. Finally, patients with and without malignant features were compared. Outcomes of interest were local recurrence-free survival (LRFS), distant metastatic-free survival (DMFS), disease-free survival (DFS), and overall survival (OS). Results: LLND+ patients (n=44) were younger with higher ASA-classifications and ypN-stages compared to LLND- patients (n=115). LLND+ patients had larger median LLNs short-axes and received more adjuvant chemotherapy (100 vs. 30%; p<0.0001). Between groups, LRFS was 97% for LLND+ versus 89% for LLND- (p=0.13). DFS (p=0.94) and OS (p=0.42) were similar. LLND was an independent significant factor for local recurrences (p=0.01) in the multi-variate analysis. Sub-analysis of patients who underwent long-course nCRT and had adjuvant chemotherapy (LLND- n=30, LLND+ n=44) demonstrated a higher LRFS for LLND+ patients (97% versus 84% for LLND-; p=0.04). DFS (p=0.10) and OS (p=0.11) were similar between groups. Seven studies were included in the systematic review. Five-year LRFS after LLND+ was improved (range 85-95%) compared to LLND- (43-89%; statistically significant in three studies). DFS was increased after LLND+ (range 61-74%) compared to LLND- (54-79%; significant in three studies). No study reported five-year overall survival benefit after LLND+ (range 72-80%; 69-91% for LLND-). In the analysis of malignant features, median LLNs short-axis was 7mm (range 5-28) for the complete cohort, of whom 60 patients (52%) had malignant features. LLNs with malignant features showed no difference in LRFS (p=0.20) but had worse DMFS (p=0.004) and OS (p=0.006) compared to those without malignant features. Cox regression analysis confirmed malignant features as an independent factor for DMFS. Conclusions: This thesis suggests that a LLND in addition to nCRT in locally advanced rectal cancer improves LRFS and DFS, and that malignant features present in enlarged LLNs are predictive for a worse DMFS. More high-quality studies are required to further explore the value of LLND and the role of malignant features in LLNs.