A clear benefit was progressively recorded during the last decades for the clinical outcome of locally advanced rectal cancer . This was due to both the integration of available evidence from literature addressing the therapeutic approaches and the optimization of each treatment modality. The role of randomized clinical trials (RCTs) is of major relevance as such evidence is the cornerstone of the process of evolution of clinical management. RCTs define what treatment approach should be considered standard of care and suggest which aspects of the established clinical practices should be questioned or deepened. Ideally, each new clinical approach should be tested and confirmed in such a way. It is also important to consider that new paradigms of approach to test clinical evidence are currently under definition and evolution, challenging and contemporary integrating the use of RCTs.