*3.2.4 Total neoadjuvant therapy (TNT)*

There has been increasing use of the non-operative approach to rectal cancer treatment since Habr-Gama et al. of Brazil published their outcomes. It removes the need for major surgery by aiming to achieve complete clinical response with neoadjuvant chemoradiotherapy and 'watch and wait' monitoring for recurrence by intensive follow-up. It not currently known whether induction chemotherapy followed by chemoradiotherapy or vice versa is the superior regimen, but the inclusion of radiotherapy significantly improves complete pathological response rates. Surgery is only undertaken for recurrent disease [46]. Until recently there were concerns most of the data came from a single centre, though it continues to gain wider acceptance and currently the subject of RCTs worldwide. As a more focused treatment, there is likely to be greater numbers of patients considering and undergoing TNT [1]. The NCCN recommends FOLFOX or CAPEOX (12–16 weeks) then long course chemoradiotherapy with capecitabine or infusional 5-FU, followed by restaging. MDTs and patients must be aware however, that local recurrence rates are around 30–35% and distant metastases of 15% occur within a year of treatment.

### *3.2.5 The malignant polyp- endoscopic approach*

The endoscopic mucosal resection (EMR) technique involves injecting a solution, traditionally saline, under the lesion to expand the submucosal space and elevate the lesion away from the muscle layer below. If the lesion does not 'lift' then this can be an important feature indicating local invasion. It may also not lift with background colitis and scarring from previous excisions or biopsies. Injections improve resections as flat lesions become more bulbous and easier to grip. EMR for lesions less the 25 mm in the rectum are usually suitable for en bloc resection [47].

Endoscopic submucosal dissection (ESD) is a relatively new technique that offers en bloc mucosal excision. This has the benefit of a high-quality pathological specimen to facilitate accurate assessment of deep and lateral margins and the depth of submucosal invasion. If R0 resection is obtained with no high risk features then recurrence rates are very low. However, ESD has a higher risk of perforation, but manageable non-surgically with endoclips. It is therefore reserved for higher risk lesions and requires a steep learning curve. It involves lifting the lesion, mucosal incision, making a 'groove' down to the muscle layer, submucosal dissection, elevation of a mucosal flap, and completing the resection en bloc [47].

### **3.3 The Conundrums: Minimising recurrence after organ-preserving treatment**

In principle, locoregional treatment is appropriate for the least invasive tumours as they are less likely to have occult lymph node metastases (1–2% for Kikuchi SM1 invasion versus 2–8% for ≥SM2). The gamble with preservation surgery is that estimation of recurrence is only assessable at histopathology.

The best outcome that will not require further treatment is a well to moderately differentiated adenocarcinoma, ≤ SM1, and R0 margins only (see **Table 3**). Therefore, the main challenges for the MDT are non-assessable excision margins (typically from cautery damage), poor differentiation, >SM1 invasion, presence of vascular invasion or R1 margins. These factors are associated with 5–18% local recurrences. If any of these features are present, the MDT ought to consider more radical treatment, specifically adjuvant therapy (such as chemotherapy with EBR and/or brachytherapy) and/ or TME excision. If TME surgery is decided, the patient must be aware that scarring from local excision may increase the risk of collateral damage to pelvic nerves, levator muscle, prostate or vagina, and increase the incidence of bleeding and low anterior resection syndrome (LARS).

One of the more challenging discussions is the possibility of residual locoregional disease after excision of a SM2 or SM3 cancer without other adverse risk factors. The patient must be aware of a 5–12% incidence of locoregional recurrence. Decisions are made to in effect halve that risk with either TME surgery or adjuvant brachytherapy +/ EBR +/ chemotherapy. The patients must be aware that TME surgery has significant morbidity of up to 10% and potentially functional concerns, such as LARS. From current literature, it is difficult to estimate the risk of recurrence by

brachytherapy+/ EBR, though suggested to be less than 5%. It remains an area in need of high quality RCTs.

For tumours staged T2, lymph-node negative and less 4cm in diameter, local excision after neoadjuvant chemoradiotherapy has been shown in clinical trials to be a safe alternative to TME surgery [48, 49] with minimal adverse impact on anorectal function 1year after surgery. Longer term data suggests some compromise to function [50]. This strategy is not routinely recommended outside of clinical trials, but may be explored at the MDT for elderly, frail patients with significant perioperative risks [51].

There is currently little evidence that healthy young patients with proven ERC should undergo organ preserving excision. TME surgery remains the 'gold standard' [52, 53]. Expert staging and treatment demand a thorough understanding of the anatomy of the rectum and the variability of characteristics in relation to gender and body habitus. Ultimately variations in presentation, patient features, and surgical factors, including the availability of therapeutic options prevents defining borders of ERC management to a viable and universal protocol. The MDT discussions must reflect that complexity and rely on up-to-date evidence of new treatments or consider enrolment into trials.

Differing treatment strategies may be appropriate depending on site of the ERC. Organ-preserving approaches are less relevant for a young patient with no comorbidities and a mid or upper ERC. However, the MDT should explore neoadjuvant therapy for a similar patient with a very low ERC, given the potential risks and impact on quality of life for a low anastomosis or abdominoperineal resection. Once the risks are discussed, an early, localised adenocarcinoma adjacent to the anal sphincter muscle may be appropriately treated with primary chemo-radiotherapy only and intense follow-up towards preserving anal sphincter function. The difference of just a few centimetres in location or millimetres in invasion can have an enormous impact on treatment options and decision-making. What remains unanswered is the longer-term impact of avoiding radical surgery.

If adverse pathology is diagnosed after local excision, proceeding to completion resection via TME surgery may be required. This may necessitate stomas, exenteration surgery for very advanced disease or adjuvant treatments. Nevertheless, those risks must be made clear to the patient before embarking on any treatment for ERC towards shared clinical decision-making and against potential litigation. Strategies to manage this particular question are quickly evolving, though likely to become a common problem with no simple answer, which mandates the MDT to be up to date with the options available.

### **3.4 Surveillance**

To date there is much variation in surveillance protocols after definitive ERC treatment. Overall, follow-up, intense or otherwise, is unlikely to significantly reduce OS. Furthermore, they are costly and cause significant patient anxiety. However, they may improve DFS and therefore quality of life while living with recurrent cancer. The recognised variations in ERC treatment will support differing approaches by MDTs on follow-up regimes. The authors recommend regular review of protocol updates and changes to patient circumstances and health condition.

The authors support an intense regime for ERCs locally treated with surgery +/ chemoradiotherapy+/ brachytherapy, in line with the Brazilian protocol proposed by Habr-Gama et al. [46]. Those with recurrent disease after local excision and subsequently treated with curative intent will require modifications to their protocol, often based on MDT preferences.

Recommended 5-year surveillance, 'intense' protocol for ERC:


If there are other high-risk polyps in the large bowel, colonoscopy may be required yearly until no further concerning polyps are identified followed by then standard bowel surveillance as per hospital guidance.
