Colorectal cancer (CRC) is the third most commonly diagnosed malignancy. It accounts for more than 50,000 deaths annually in the US, ranking second among cancers in terms of mortality. The primary histologic subtype is that of the adenocarcinoma with intestinal differentiation, arising from the mucosa and its glandular formations. Rectal cancer, in specific, comprises approximately 30% of CRC cases, with a higher incidence in men (~ 60%) than in women (~40%) (Siegel et al., 2022 Jan). In Southern Europe, cases of rectal cancer reach 22 per 100.000 population and the incidence ratio among men and women is that of 2:1, while in South Central Asia age-standardized incidence rate per 100,000 is hardly 5, indicating that factors such as lifestyle and diet contribute significantly to the probability of rectal cancer (Sung et al., 2021 May).

Early stages of rectal cancer can be effectively treated with surgery alone. Locally advanced disease, however, demands a multimodal approach due to the high rates of locoregional recurrences and development of metastasis. Such tumors exhibit extramural invasion and/or nodal involvement. Clinical T4 or N2 stage, enlarged pelvic nodes, mesorectal fascia involvement, or extramural vascular invasion define a subgroup of locally advanced tumors with high-risk features (Bahadoer et al., 2021 Jan).

Accurate preoperative staging is essential to properly guide treatment decisions. Before the early 2000s CT, mostly, and, in part, MRI were used to determine the extent of mural invasion and potential involvement of lymph nodes. The MERCURY trial and its subsequent 5-year follow-up update, published in 2006 and 2014, respectively, first demonstrated the significance of MRI imaging in assessing the circumferential resection margin status and, eventually, predicting clear resection margins (MERCURY Study Group, 2006 Oct 14, Taylor et al., 2014 Jan 1). Following these findings, more recent studies have set MRI as the gold standard procedure to clinically stage rectal cancer patients before treatment.

The treatment of patients with locally advanced rectal cancer has been continuously evolving during the past decades when surgical innovation techniques were gradually placed in a larger therapeutic frame that embraces radiotherapy (RT) and chemotherapy. What is the best sequence of such combinations remains under intense clinical evaluation. Approximately 90% of patients with rectal cancer will be alive 3 years after neoadjuvant chemoradiotherapy (CRT) followed by surgery. However, 3-year disease-related treatment failure is observed in one fourth of advanced rectal cancer cases. Even after Total Neoadjuvant Therapy (TNT), which is associated with high complete response rates, a significant proportion of patients with advanced low rectal cancer will eventually be treated with abdominoperineal excision followed by permanent colostomy. Thus, in parallel to overall survival (OS), the quality of life of survivors should be equally considered in clinical studies. In the current study, we review the past and the present of rectal cancer therapy, highlighting the sequence of steps that were followed to adjust and improve the treatment offered to patients with locally advanced rectal cancer through many decades of clinical experimentation, observation, hypothesis and the continuous development and conduct of new clinical trials to confirm eventual benefits. Moreover, we outline the recent questions that have risen from the clinical research and the forthcoming developments expected from on-going clinical trials, including attempts to identify subgroups of patients that would benefit from immunotherapy or even the omission of surgery, RT or chemotherapy.

The EMBASE and MEDLINE databases were used for literature search, applying the scientific terms “rectal adenocarcinoma”, “surgery”, “radiotherapy”, “chemotherapy”, “preoperative”, “neoadjuvant”, “immunotherapy” and “targeted therapy”. Randomized phase III trials were included for critical presentation in this review. Selected phase II and translational studies that changed or opened the road for future developments were also included.