Locally advanced rectal cancer (LARC) is commonly characterized as cT3 or cT4 primary tumor or tumor with nodal metastases. The standard treatment of LARC involves neoadjuvant chemoradiotherapy (nCRT) followed by surgical resection and adjuvant chemotherapy or total neoadjuvant therapy (TNT), consisting of CRT and neoadjuvant chemotherapy, followed by surgical treatment [1]. It has replaced the formerly used post-operative chemoradiotherapy as randomized trials have shown that pre-operative irradiation is more effective in reducing the risk of local recurrence and causes fewer early and late radiation-induced complications [2]. However, surgical treatment entails possible complications such as postoperative ileus [3], surgical site infection [4], wound dehiscence, anastomotic leakage and risk of a permanent stoma [5]. In addition, low anterior resection sy ndrome (LARS) and sexual dysfunction following surgical resection affect a high percentage of patients [[6], [7], [8]]. For this reason, organ preserving strategies following nCRT and TNT are increasingly being investigated. There are three possible scenarios following the primary treatment (nCRT or TNT) of LARC. In the group of patients with clinical complete response (cCR) organ preserving watch-and-wait approach consisting of close surveillance is gaining recognition particularly in high-risk surgical patients [9,10]. Another scenario is incomplete response requiring radical surgery [1]. In some cases, there is a near-cCR to nCRT or TNT [11]. Occasionally, however, residual polypoid lesion that appears clinically benign remains in the rectum. Up until recently, this was an indication for radical surgery or local surgical removal; however, an emerging alternative involving advanced endoscopic techniques is now being considered. Further investigation in these scenarios consists of thorough endoscopic evaluation and rectal magnetic resonance imaging (MRI) to stage the lesion. In case of no evidence of invasive disease on rectal MRI and no features of advanced disease on endoscopic evaluation (when adenoma or early cancer is suspected), endoscopic treatment may be considered [12]. This narrative review aims to discuss the potential role of endoscopic treatment in cases of residual rectal neoplasia following neoadjuvant radiotherapy.

The neoadjuvant chemoradiotherapy plus adjuvant chemotherapy provides pathological complete response in 15% of patients, whereas the total neoadjuvant therapy (TNT) achieves it in 30% of patients [13]. The watch and wait strategy in patients with LARC who achieve a cCR (disappearance of the tumor and clinically positive lymph nodes) after neoadjuvant therapy offers an opportunity for patients to avoid major resection surgery - total mesorectal excision (TME) [14]. However, evidence on the safety of this method from randomized trials is lacking. Promising results have been shown in several meta-analyses of observational studies and one international registry study [[15], [16], [17]]. In the registry study of 880 patients with a complete clinical response (cCR) a local regrowth was observed in 25.2% of patients after a median of 2 years follow-up [17].

Since there is no widely accepted protocol for periodic follow-up examinations in patients with cCR or near-cCR after nCRT, this part of the watch-and-wait strategy has been a major clinical challenge. An international consensus has not been reached on imaging strategies and timing to identify a complete clinical response, or follow-up protocols for timely detection of tumour regrowth. Several available studies suggested that a combination of digital rectal examination (DRE), endoscopy and MRI are viable tests to assess response to nCRT [[18], [19], [20]]. These studies commonly defined cCR at endoscopy as white scar with or without telangiectasia [19,20] and near-cCR as presence of flat ulcer with smooth edges [19]. Here we propose a regimen used as part of our current practice and the NOM-3 clinical trial (NCT05241574). At 12–15 weeks after initiation of nCRT a patient undergoes DRE as triage tests (Fig. 1). Patients with persistent tumor (incomplete response, Table 1, type 5) are referred for surgery. Patients with suspected cCR or near-cCR on DRE are referred for endoscopy and MR imaging for final diagnosis. A complete photo documentation at each endoscopy examination is mandatory.

Patients are defined as cCR when endoscopy shows a clear scar and/or telangiectasias at endoscopy (Table 1, type 1) and MRI confirms complete disappearance of the tumor. In those patients DRE, endoscopic assessment and MRI are performed every 3 months during the first 2 years after treatment.

Patients are defined as near-cCR (Table 1) when endoscopy shows one of the two possible scenarios: shallow ulceration without infiltration (type 2) or superficial lesion with an appearance of a benign adenoma (type 3, Fig. 2). All those patients undergo repeat DRE, endoscopy and MRI at 2 months. For patients with superficial and deep ulceration (type 2 and 4) four possible scenarios are possible: (i) regression to complete response - scar or telangiectasias (type 1), (ii) further regression, but residual shallow ulceration still persists (type 2) – this could indicate rather post-radiation nature, (iii) endoscopically stable lesions (type 2 or 3), (iv) progression of lesions compared to previous examination (type 5). If the lesion is stable or regress further follow up at 2 months is suggested. If the lesion progresses a patient is referred to surgery. Patient with a superficial lesion (type 4 response, Fig. 2) confirmed at subsequent 2 months follow up requires further treatment described in the next section.

It is also important to emphasize nuances of histopathological assessment of post-radiation tissue changes in the follow up decision process. Surviving cancer cells are most often localized in a muscle layer of a rectum [21]. Superficial collection of biopsies may yield a false-negative result. Several weeks after irradiation, cancer cells that are inactive may look “alive” under the microscope. It takes several weeks for them to break down. Taking biopsies a few weeks after irradiation may result in false-positive findings. For the above reasons, it is generally not recommended to routinely collect specimens up to 6 months after irradiation in patients with cCR or near-cCR which is stable or regresses. However, the biopsies should be taken in case of regrowth after cCR, lesion progression in a patient with near-cCR or lack of regression at 6 months follow up in a patient with near-cCR.

The term “residual rectal neoplasia” refers to remnant neoplastic cells which persist despite definitive CRT. Cancer cells which survive lead to the reestablishment of cancerous growth in the treated area [22]. Such recurrence occurs at or close to the primary site of the rectal tumor. Local regrowth is typically identified through DRE, MRI, endoscopic evaluation and histopathological analysis and it presents a clinical challenge which requires careful assessment and planning of treatment to achieve optimal outcomes [23]. Traditionally, salvage surgery, such as total mesorectal excision (TME), was the standard treatment for these patients [9,24]. However, two mechanisms complicate the assessment of residual rectal neoplasia. Firstly, nCRT leads to replacement of cancer cells by fibroinflammatory cells within residual tissue [25]. Secondly, since adenomatous (benign) tissue is less sensitive to nCRT, visible residual rectal neoplasia after primary treatment does not necessarily contain deep invasive disease [25]. Nevertheless, given that there are no unequivocal optical tools or imaging modalities to differentiate between malignant and adenomatous or fibrous tissue, such polypoid residual neoplasia raises justified concern about a risk of disease persistence.

The risk of residual rectal cancer after nCRT can vary based on several factors. While specific criteria can depend on the individual patient and the treatment protocol, here are some general criteria that may indicate an increased risk of residual disease:

Clinical Tumor Stage Before Treatment: patients with higher initial clinical tumor stages (T3 or T4) tend to have a higher risk of residual cancer after CRT [15,26,27].

Tumor Size: larger tumors often carry a higher risk of residual disease as they may not respond as effectively to the treatment [28].

Lymph Node Involvement: patients with positive lymph nodes before CRT may be at an increased risk of residual disease [26].

Histological Type: some histological types of rectal cancer (like mucinous component) may be more resistant to treatment, leading to a higher risk of residual disease [29].

The concept of salvage endoscopic treatment in LARC after nCRT consists of resecting residual neoplastic tissue. This provides an opportunity for pathological assessment of the specimen, evaluation of the response to neoadjuvant therapy, and removal of residual neoplastic tissue (if present). Advanced endoscopic techniques have dynamically developed in the past decade creating new opportunities in removing rectal lesions. Endoscopic submucosal dissection (ESD) is a procedure permitting en-bloc resection of superficial neoplasms regardless of the size of the lesion [30]. The main principle of this technique is gradual dissection through the submucosal which permits to remove the lesion with safety margins. The en bloc resection enables precise pathologic assessment of the specimen including the depth of mural invasion and other risk factors of lymph nodes metastasis such as lymphovascular invasion or tumor budding [31]. Another emerging procedure is endoscopic intermuscular dissection (EID). This novel technique consists of dissection in between the circular and longitudinal layers of the muscularis propria allowing complete removal of rectal lesions with suspected deep submucosal invasion maintaining the rectal wall intact. Since the alternative treatment of deep invasive rectal T1 cancer is surgical approach which is associated with severe complications, EID creates an opportunity of safe organ preserving management particularly for high-risk surgical patients [32]. Endoscopic full-thickness resection (eFTR) is another recently developed resection technique allowing minimally invasive treatment of colorectal lesions ≤30 mm unsuitable for other endoscopic resection techniques [33]. It allows full-thickness tissue resection and perforation closure with an over-the-scope clip (OTSC). This endoscopic procedure which provides opportunity for assessment of all the layers of colorectal wall. However, eFTR in the rectum may affect the outcomes of future surgical management if needed [32]. The optimal site for full thickness rectal excision is an area where there is a substantial presence of mesenteric fat and minimal critical structures beyond this fat layer, predominantly found in the posterior wall of the rectum. Conversely, the most challenging and risky site, particularly in the extraperitoneal region of the rectum, is the distal anterior wall. In this location, mesenteric fat is scarce, and structures such as the vagina or the prostatic urethra are only separated from the muscular layer of the rectum by a notably thin septum. This anatomical configuration presents significant challenges for safe and effective excision [34].

Salvage endoscopic treatment is technically challenging because of radioation-induced changes at the site of the lesion which can increase the risk of complications. At the tissue level the first histological changes such as oedema or hyperemia caused by radiation can be seen a few hours after CRT. A few weeks after CRT infiltration of leukocytes and occlusive vasculitis triggered by foam cell invasion of the innermost layer of a blood vessel (intima) and hyaline thickening of the media of arterioles are observed [35]. This mechanism leads to ischemia which, along with cellular apoptosis and fibroblast and inflammatory cell infiltration, can result in extensive fibrosis of the intestinal wall and chronic inflammatory changes [36]. Furthermore, some studies show that the luminal diameter of submucosal arteries is increased due to radiation-induced ischemia which leads to accumulation of cytokines, growth factors and reperfusion in the tissue [37]. This phenomenon may cause more severe bleeding during endoscopic procedures. Radiation-induced fibrosis of the muscularis mucosa and submucosal layers as well as increased luminal diameter of submucosal arteries represent significant difficulties in endoscopic management. These post-radiation changes make resection procedures technically more challenging and may lead to more frequent and severe complications. However, Leung et al. [12] proved that salvage ESD after radiation is technically feasible with no significant differences in adverse events rates between salvage and standard (without previous nCRT) groups. They observed extensive fibrosis in all the lesions after nCRT but did not experience any significant bleeding events or need of increased use of hemostasis in the salvage group. Special modification of the resection technique may be required to technically facilitate the removal of scarred lesions. The pocket-creation method has a potential to address insufficient submucosal lift of scarred lesion [38]. A traction methods can be helpful and reduce the time of the procedure. Finally, a tapered distal cap might facilitate access to narrow spaces during ESD [12]. EID and eFTR may potentially overcome the problem of extensive submucosal fibrosis by cutting at deeper layers of rectal wall, though the data to support their use in this setting is missing.