Early‐stage low rectal cancer – re‐thinking the standard of care

Rectal cancer is a complex disease with evolving treatment options. Locally advanced rectal cancer (LARC) represents a subgroup that has seen much attention over the past few decades, with the best evidence now supporting Total Neoadjuvant Therapy (TNT) as a primary treatment modality, owing to trials demonstrating improved disease-free survival and complete clinical response rates (cCR).1-3 In addition, non-operative management and organ preservation have emerged as feasible options for many of these patients,4, 5 with recently published data demonstrating acceptable survival outcomes, improved quality of life, reduced cost and feasible salvage surgery in cases of local regrowth.6-8 Early-stage rectal cancer (cT1–T3, N0) has perhaps been overshadowed by its locally advanced counterpart; however, it also represents a uniquely heterogenous and challenging entity to manage. Upfront surgical resection with total mesorectal excision (TME) has been the recommended mainstay treatment for most early rectal cancers,9, 10 affording patients good local recurrence and survival outcomes. However, radical TME resection carries significant risks, with important ramifications for quality of life and function, as well as the possibility of a permanent stoma depending on tumour height and anastomotic complications. Accordingly, organ preservation has garnered increasing attention in early rectal cancer, particularly for low-lying tumours. For T1 disease, local excision techniques such as transanal endoscopic microsurgery are common practice, although oncological outcomes are not always ideal and true staging is only possible after excision.11 In the case of T2–T3 disease, clinicians and patients are increasingly turning to neoadjuvant therapy in the hopes of achieving cCR and organ preservation. Whilst not reflected in guidelines or supported by high-quality evidence, this option has clearly permeated into clinical practice, with a recent multi-centre retrospective study from the United States showing that over half of patients with early-stage rectal cancer undergoing proctectomy had received some form of neoadjuvant treatment.12 Unpublished local institutional data of patients with early low rectal cancers who have declined upfront surgical resection and undergone TNT have demonstrated cCR rates in the vicinity of 60%.13 Further to this, the phase II NEO study is an example of a trial pushing the boundaries in organ preservation. Here, patients with T1–T3ab rectal cancer were given neoadjuvant chemotherapy with the aim of tumour downstaging and organ preservation via endoscopic resection. Whilst preliminary results have shown a 79% organ preservation rate and 2-year locoregional relapse-free survival of 90%,14 such approaches may still undertreat under-staged patients and survival outcomes may not have been as high as expected. This segues to another important and often overlooked issue in early rectal cancer – the current limitations of locoregional radiological staging. A retrospective study of stage I rectal cancer patients who had not received preoperative therapy revealed a tumour upstaging rate of around 10% and a nodal upstaging rate of around 20% following surgery.15 Similarly, another cohort study of patients with Stage I rectal cancer who had undergone resection identified that ~25% of patients had unrecognized T3 disease or nodal involvement. In this cohort, nodal disease was associated with worse outcomes despite the receipt of adjuvant therapy,16 which is not particularly surprising given that adjuvant chemotherapy has very limited benefit in rectal cancer patients. Additionally, low tumours preferentially drain to the lateral compartment, with lateral node involvement being observed in around 10% of these tumours,17 and in the West, this lateral compartment is not routinely dissected or treated in early rectal cancer. Such findings lend merit to the notion that there may be an oncological advantage in treating low, early rectal cancer patients with neoadjuvant therapy, allowing capture of under-staged and under-treated patients. While neoadjuvant therapy for subset groups of early-stage rectal cancer is attractive, it must be stressed that well-designed trials exploring its efficacy and safety are crucial and currently sparsely available in the literature. A promising trial underway is the Japanese JCOG2010 TOWARd phase II/III study, which is enrolling patients with cT2–T3 N0 rectal cancer to receive consolidation TNT (cTNT), with the aim of assessing organ preservation and survival outcomes.18 A number of randomized trials addressing the use of neoadjuvant therapy and local excision (LE) in early rectal cancer have already been published, with a recent meta-analysis comparing this with TME demonstrating no significant difference in disease-free survival (DFS), overall survival (OS) or local recurrence.19 However, caution in adopting the results of such trials into clinical practice is required as survival outcomes may not be as high as expected in both intervention and standard care groups. Considering the historical results of COLOUR II for rectal cancer patients undergoing open TME, Stage II rectal cancer was associated with a 3-year DFS of around 75% and a 3-year OS under 90%.20 In light of modern TNT affording patients with much more advanced cancer a 3-year DFS and OS in the territory of 75% and 90–95%, respectively, we would argue for a reconsideration of what threshold rates for survival outcomes should be deemed acceptable in early-stage rectal cancer. This sets the stage for an ongoing need for auditing of outcomes in early-stage rectal cancer treated with upfront TME, as well as an avenue for potentially improving prospects for organ preservation and survival outcomes in this important group of patients. Translating the apparent superiority of cTNT for organ preservation seen in LARC, along with the possible survival benefits, our institution is currently in the early phases of establishing a multi-centre phase II trial investigating the efficacy of a modified cTNT regime in achieving cCR and organ preservation in patients with low cT2–T3 N0 M0 rectal adenocarcinoma (‘The EARLY-TNT Trial’). This study will hopefully provide a valuable foundation of evidence for a novel option for early-stage rectal cancer patients, and fuel further local and international studies. Open access publishing facilitated by The University of Adelaide, as part of the Wiley - The University of Adelaide agreement via the Council of Australian University Librarians.