Tailored total neoadjuvant therapy for locally advanced rectal cancer: One size may not fit for all!

Abstract

While current neoadjuvant protocols have proven benefits on local control for majority of patients with locally advanced rectal cancer, there are certain clinical conditions that require future advances for improving the outcomes. Total neoadjuvant therapy incorporates systemic chemotherapy planned within standard neoadjuvant protocols either before or after radiotherapy for locally advanced rectal cancer as a whole. Enhanced compliance with planned oncological therapy, tumour downstaging, administration of chemotherapy at the earliest time in the disease course to help assessing chemosensitivity are the proposed benefits of total neoadjuvant therapy in patients with locally advanced rectal cancer. Patient selection criteria for administration of total neoadjuvant therapy in the recent guidelines are unclear. Since current literature is inconclusive for the optimal sequence and type of radiotherapy and chemotherapy, premature incorporation of total neoadjuvant therapy for all locally advanced rectal cancers may result in overtreatment and subsequently toxicity. This article aims to discuss the current literature and to propose a future perspective by considering real-life scenarios reflecting patients' needs for treatment of locally advanced rectal cancer.

Personalized total neoadjuvant therapy (pTNT) for advanced rectal cancer with tailored treatment sequencing based on clinical stage at presentation

“…It is clear from the data above that, compared with standard care, TNT offers better rates of primary tumour response, organ preservation and disease free survival in patients with locally advanced rectal cancer 13,28,30,34 . However, while optimal treatment sequencing is yet undefined, consolidation chemotherapy likely offers improved primary response rates but at the expense of increased chemotherapy toxicity (and therefore compliance) 13,16 . Therefore, it may be rational to tailor the order of TNT to disease biology 35,36 .…”

“…13,28,30,34 However, while optimal treatment sequencing is yet undefined, consolidation chemotherapy likely offers improved primary response rates but at the expense of increased chemotherapy toxicity (and therefore compliance). 13,16 Therefore, it may be rational to tailor the order of TNT to disease biology. 35,36 In the current study, a two-schema approach to TNT treatment addresses sequence administration by considering tumour biology and patient disease risk profile at presentation and attempts to prioritize compliance with the most vital component of TNT treatment.…”

“…While multiple recent randomized trials have provided supporting data for the safety and effectiveness of TNT, 9,11–14 the data remain inconclusive regarding optimal sequencing of chemotherapy and radiotherapy. Furthermore, it is unclear whether one form of TNT is suitable for all patients with advanced rectal cancer or whether a risk‐adapted treatment strategy based on clinical staging (distant or locally advanced) is more appropriate 15,16 . The aim of this prospective study was to assess short term outcomes of a personalized total neoadjuvant treatment (pTNT) protocol, with tailored treatment sequencing based on clinical stage at presentation.…”

“…Furthermore, it is unclear whether one form of TNT is suitable for all patients with advanced rectal cancer or whether a risk-adapted treatment strategy based on clinical staging (distant or locally advanced) is more appropriate. 15,16 The aim of this prospective study was to assess short term outcomes of a personalized total neoadjuvant treatment (pTNT) protocol, with tailored treatment sequencing based on clinical stage at presentation.…”

Editor's choice – June 2022

“…The past decade has seen a particular focus on a shift in neoadjuvant therapy paradigms to one of total neoadjuvant therapy (TNT) with the aim of combating disseminated micrometastatic disease early in the treatment pathway and especially before complications from surgery may arise. The optimal patient selection criteria for TNT regimens remains unclear [1].…”