ABSTRACT: Approximately one-third of all newly diagnosed colorectal cancer (CRC) is composed of rectal cancer, with the incidence rising in younger patients. The principal neoadjuvant treatments consist of neoadjuvant short-course radiotherapy and long-course chemoradiation. Locally advanced rectal cancer (LARC) is particularly challenging to manage given the anatomical constrictions of the pelvis and the risk for local recurrence. In appropriately treated patients, 5- and 10-year overall survival is estimated at 60 and 50%, respectively. The prognosis for LARC has improved in recent years with more access to screening, advances in surgical techniques, and perioperative care. Furthermore, the refinement of the multidisciplinary team with combined-modality management strategies has improved outcomes. These advancements have been augmented by significant improvements in the understanding of the underlying tumor biology. However, there are many instances where patient outcomes do not match those for their tumor stage and accurate prognostic information for individual patients can be difficult to estimate owing to the heterogeneous nature of LARC. Many new combinations of chemotherapy with radiotherapy, including total neoadjuvant therapy with targeted therapies that aim to diminish toxicity and increase survival, are being evaluated in clinical trials. Despite these advances, local recurrence and distant metastasis remain an issue, with one-third of LARC patients dying within 5 years of initial treatment. Although much of the new pathological, molecular genetics, and immunological biomarkers allow refinement in the classification and prognostication of CRC, the relative importance of each of these factors with regards to the development and progression of LARC remains incompletely understood. These factors are often insufficiently validated and seldom consider the individual characteristics of the host, the tumor and its location, the local available expertise, or the probable location of recurrence. Appreciating the mechanisms behind these differences will allow for a more comprehensive, personalized approach and more informed treatment options, leading to ultimately superior outcomes. This review aims to first outline the current multidisciplinary context in which LARC care should be delivered and then discuss how some key prognosticators, including novel histopathological, molecular genetics, and immunological biomarkers, might fit into the wider context of personalized LARC management in the coming years.
