Selecting a TNT Schedule in Locally Advanced Rectal Cancer: Can We Predict Who Actually Benefits?

Abstract

Many consider the standard of care for locally advanced rectal cancer (LARC) to be preoperative chemoradiotherapy, radical surgery involving a total mesorectal excision, and post-operative adjuvant chemotherapy based on the pathology of the specimen. The poor impact on distant control is a major limitation of this strategy, with metastasis rates remaining in the 25–35% range and recovery after radical surgery leading to reluctance with prescription and inconsistent patient compliance with adjuvant chemotherapy. A second limitation is the low rate of pathologic complete response (pCR) (around 10–15%) despite multiple efforts to potentiate preoperative chemoradiation regimens, which in turn means it is less effective at achieving non-operative management (NOM). Total neoadjuvant treatment (TNT) is a pragmatic approach to solving these problems by introducing systemic chemotherapy at an early timepoint. Enthusiasm for delivering TNT for patients with LARC is increasing in light of the results of published randomized phase III trials, which show a doubling of the pCR rate and a significant reduction in the risk of subsequent metastases. However, there has been no demonstrated improvement in quality of life or overall survival. A plethora of potential chemotherapy schedules are available around the radiotherapy component, which include preoperative induction or consolidation with a range of options (FOLFOXIRI, FOLFOX, or CAPEOX,) and a varying duration of 6–18 weeks, prior to long course chemoradiation (LCCRT) or consolidation NACT following short-course preoperative radiation therapy (SCPRT) using 5 × 5 Gy or LCCRT using 45–60 Gy, respectively. The need to maintain optimal local control is a further important factor, and preliminary data appear to indicate that the RT schedule remains a crucial issue, especially in more advanced tumors, i.e., mesorectal fascia (MRF) invasion. Thus, there is no consensus as to the optimum combination, sequence, or duration of TNT. The selection of patients most likely to benefit is challenging, as clear-cut criteria to individuate patients benefiting from TNT are lacking. In this narrative review, we examine if there are any necessary or sufficient criteria for the use of TNT. We explore potential selection for the individual and their concerns with a generalized use of this strategy.

Surgical Outcomes in Total Neoadjuvant Therapy for Rectal Cancer versus Standard Long Course Chemoradiation

“…33 The reduction of distant metastasis is attributed to the early treatment of micrometastasis with TNT. 34 Indeed, oncological results from TNT have been promising, with RCTs as well as multiple meta-analyses on the topic showing statistically significant improvement in pathologic complete response rates and disease-free survival. [11][12][13][14] TNT has also shown no difference in R0 resection rates and treatment toxicity in these analyses, and this has led some authors to conclude that TNT should be considered the new standard of care in the multimodal treatment of rectal cancers.…”

“…This lends further weight to early systemic therapy improving control of disease to reduce risk of progression during neoadjuvant treatment. 34 Some authors have previously attributed the oncological benefits of TNT to better chemotherapy compliance 37 as poor compliance may be the reason for distant failure in the management of rectal cancer. 38,39 A recent network meta-analysis showed no difference in compliance to chemotherapy whatever the neoadjuvant treatment regimen 40 was-and this is further evidence for the efficacy of TNT as it provides improved disease-free survival without any difference in compliance.…”

Recent advances in rectal cancer treatment – are we on the right track?

“…Over several decades, advances have been seen in the treatment of rectal cancer resulting in a marked reduction in the risk of locoregional recurrences (LRRs), but without any improved overall survival (OS) in the trials ( 1 ). Population data have, however, revealed improved OS during the past decades ( 2 , 3 ).…”

Validated Pretreatment Prediction Models for Response to Neoadjuvant Therapy in Patients with Rectal Cancer: A Systematic Review and Critical Appraisal

“…The chance of achieving a complete response after neoadjuvant therapy is partly dependent on the neoadjuvant treatment regimen. In patients with locally advanced rectal cancer (LARC), CRT results in pCR rates of 10-30% [3], whereas TNT increases this chance [2][3][4][5], with better outcomes after the use of consolidation therapy versus induction therapy [20,21]. Nevertheless, TNT is associated with a higher risk of toxicity [20], which may impair patients' quality of life.…”

“…In patients with locally advanced rectal cancer (LARC), CRT results in pCR rates of 10-30% [3], whereas TNT increases this chance [2][3][4][5], with better outcomes after the use of consolidation therapy versus induction therapy [20,21]. Nevertheless, TNT is associated with a higher risk of toxicity [20], which may impair patients' quality of life. Careful selection of patients for type of neoadjuvant regimen is therefore essential.…”