Total neoadjuvant therapy for the treatment of locally advanced rectal cancer: a systematic minireview

Abstract

Colorectal carcinoma is the second leading cause of cancer-related deaths, and indeed, rectal cancer accounting for approximately one third of newly diagnosed patients. Gold standard in the treatment of rectal cancer is a multimodality approach, aiming at a good control of the local disease. Distant recurrences are the major cause of mortality. Currently, Locally Advanced Rectal Cancer (LARC) patients undergo a combined treatment of chemotherapy and radiotherapy, followed by surgery. Eventually, more chemotherapy, namely adjuvant chemotherapy (aCT), may be necessary. Total Neoadjuvant Therapy (TNT) is an emerging approach aimed to reduce distant metastases and improve local control. Several ongoing studies are analyzing whether this new approach could improve oncological outcomes. Published results were encouraging, but the heterogeneity of protocols in use, makes the comparison and interpretation of data rather complex. One of the major concerns regarding TNT administration is related to its effect on larger and more advanced cancers that might not undergo similar down-staging as smaller, early-stage tumors. This minireview, based on a systematic literature search of randomized clinical trials and meta-analysis, summarizes current knowledge on TNT. The aim was to confirm or refute whether or not current practice of TNT is based on relevant evidence, to establish the quality of that evidence, and to address any uncertainty or variation in practice that may be occurring. A tentative grouping of general study characteristics, clinical features and treatments characteristics has been undertaken to evaluate if the reported studies are sufficiently homogeneous in terms of subjects involved, interventions, and outcomes to provide a meaningful idea of which patients are more likely to gain from this treatment.

Comprehensive analysis of transient receptor potential channels-related signature for prognosis, tumor immune microenvironment, and treatment response of colorectal cancer

“…Although neoadjuvant treatment followed by radical surgery is the standard treatment for locally advanced rectal cancer (LARC) ( 18 ), the pathological complete response rate and survival benefit remain unsatisfactory and questionable ( 5 ). Hence, a widely recognized biomarker is the key to selecting a potential beneficiary.…”

“…Although neoadjuvant treatment and immune checkpoint inhibitors (ICIs) play an increasing role in CRC management, not all patients benefit from them ( 18 , 19 ). In addition, no biomarkers exist to screen their potential benefit ( 18 ).…”

“…Although neoadjuvant treatment and immune checkpoint inhibitors (ICIs) play an increasing role in CRC management, not all patients benefit from them ( 18 , 19 ). In addition, no biomarkers exist to screen their potential benefit ( 18 ). Evidence showed that tumor immune microenvironment (TIME) ( 20 ), which is associated with TRPC via polarization of macrophages, recruitment of chemokines, and activation of effector cells, strongly influences cancer treatment response ( 20 , 21 ).…”

Survival outcomes of different neoadjuvant treatment regimens in patients with locally advanced rectal cancer and MRI‐detected extramural venous invasion

“…In addition, neoadjuvant chemoradiotherapy (nCRT) is now commonly offered to these patients. 8 Furthermore, intensification of neoadjuvant treatment with induction or consolidation chemotherapy before surgery, an approach known as total neoadjuvant treatment (TNT), 9 has been shown to significantly decrease the probability of disease-related systemic treatment failure in patients with LARC. 10,11 However, the need for radiotherapy in patients with LARC remains controversial, 12 particularly for those without adverse prognostic indicators.…”

Timing of additional neoadjuvant chemotherapy in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy and total mesorectal excision

“…Consequently, recent treatment strategies for patients with LARC have focused instead on giving additional cycles of chemotherapy prior to TME [ 2 , 8 ]. The intensification of preoperative treatment with standard dose polychemotherapy administration before surgery, known as total neoadjuvant treatment (TNT), has shown encouraging results [ 9 ]. Moreover, the improvement in radiological field could allow to predict pathological response after neoadjuvant treatment; in particular, the assessment of 18F-FDG PET-CT uptake decrease, could guide the choice of administered therapy [ 10 ].…”