Simple SummaryLymphatic spreading is a main driver of metastasis and, thus, associated death in colon cancer. Therefore, resecting all metastatic lymph nodes is vital for cancer-free survival. Although resection within established resection lines provides a good lymph node yield, aberrant lymphatic drainage pathways may be missed. Lymphatic mapping can compensate for this shortcoming. Different methods for tracing lymphatic drainage exist, such as radiocolloid tracers, ink, and fluorescent tracers. Tracers can be applicated either during surgery or before surgery through colonoscopy, giving the tracer more time to travel through the lymphatic system and highlighting more distant tumor-draining lymph nodes. This review aims to assess which protocol best maps the lymphatic drainage pathway and thus enables an optimized, personalized approach for curative resection.AbstractAn optimized lymph node yield leads to better survival in colon cancer, but extended lymphadenectomy is not associated with survival benefits. Lymphatic mapping shows several colon cancers feature aberrant drainage pathways inducing local recurrence when not resected. Currently, different protocols exist for lymphatic mapping procedures. This meta-analysis assessed which protocol has the best capacity to detect tumor-draining and possibly metastatic lymph nodes. A systematic review was conducted according to PRISMA guidelines, including prospective trials with in vivo tracer application. The risk of bias was evaluated using the QUADAS-2 tool. Traced lymph nodes, total resected lymph nodes, and aberrant drainage detection rate were analyzed. Fifty-eight studies met the inclusion criteria, of which 42 searched for aberrant drainage. While a preoperative tracer injection significantly increased the traced lymph node rates compared to intraoperative tracing (30.1% (15.4, 47.3) vs. 14.1% (11.9, 16.5),p= 0.03), no effect was shown for the tracer used (p= 0.740) or the application sites comparing submucosal and subserosal injection (22.9% (14.1, 33.1) vs. 14.3% (12.1, 16.8),p= 0.07). Preoperative tracer injection resulted in a significantly higher rate of detected aberrant lymph nodes compared to intraoperative injection (26.3% [95% CI 11.5, 44.0] vs. 2.5% [95% CI 0.8, 4.7],p< 0.001). Analyzing 112 individual patient datasets from eight studies revealed a significant impact on aberrant drainage detection for injection timing, favoring preoperative over intraoperative injection (OR 0.050 [95% CI 0.010–0.176],p< 0.001) while indocyanine green presented itself as the superior tracer (OR 0.127 [95% CI 0.018–0.528],p= 0.012). Optimized lymphatic mapping techniques result in significantly higher detection of aberrant lymphatic drainage patterns and thus enable a personalized approach to reducing local recurrence.