Predictive model for sphincter preservation in lower rectal cancer

Abstract

BACKGROUND

Low rectal cancer poses a significant surgical challenge because of its close proximity to the anal sphincter, often requiring radical resection with permanent colostomy to achieve oncological safety. Revisited rectal anatomy, advances in surgical techniques and neoadjuvant therapies have enabled the possibility of sphincter-preserving procedures, however, it is uniformly not applicable. Selecting appropriate candidates for sphincter preservation is crucial, as an ill-advised approach may compromise oncological outcome or lead to poor functional outcomes. Currently there is no consensus - which clinical, anatomical, or molecular factors most accurately predict the feasibility of sphincter-preserving surgery (SPS) in this subset of patients. By identifying these predictors, the study seeks to support improved patient selection, enhance surgical planning, and ultimately contribute to better functional and oncological outcomes in patients with low rectal cancer.

AIM

To identify predictive factors that determine the feasibility of SPS in patients with low rectal cancer.

METHODS

A comprehensive literature search was conducted using PubMed/MEDLINE databases. The search focused on various factors influencing the feasibility of SPS in low rectal cancer. These included patient-related factors, anatomical considerations, findings from different imaging modalities, advancements in diagnostic tools and techniques, and the role of neoadjuvant chemoradiotherapy. The relevance of each factor in predicting the potential for sphincter preservation was critically analyzed and presented based on the current evidence

RESULTS

Multiple studies have identified a range of predictive factors influencing the feasibility of SPS in low rectal cancer. Patient-related factors include age, sex, preoperative continence status, comorbidities, and body mass index. Anatomical considerations, such as tumor distance from the anal verge, involvement of the external anal sphincter, and levator ani muscles, also play a critical role. Additionally, a favourable response to neoadjuvant chemoradiotherapy has been associated with improved suitability for sphincter preservation. Several biomarkers, such as inflammatory markers like interleukins and C-reactive protein, as well as tumor markers like carcinoembryonic antigen, are important. Molecular markers, including BRAF and KRAS mutations and microsatellite instability status, have been linked to prognosis and may further guide decision-making regarding sphincter-preserving approaches. Artificial intelligence (AI) can further add in to select an ideal patient for sphincter preservation.

CONCLUSION

SPS is feasible in low rectal cancer and depends on patient factors, tumor anatomy and biology, preoperative treatment response, and biomarkers. In addition, tools and technology including AI can further help in selecting an ideal patient for long term optimal outcome.

Key Words: Low rectal cancer; Surgery; Sphincter preservation; Predictive model; Factors

Core Tip: Managing lower rectal cancer is challenging due to its anatomical complexity, often resulting in the need for a permanent stoma. Sphincter preservation significantly improves patients' quality of life. It is crucial to identify key factors that influence the feasibility of sphincter-sparing surgery while ensuring favourable long-term oncological and functional outcomes. Keeping the predictive factors in mind, accurate identification of the ideal subset of patients for sphincter preservation is possible, which may obviate unnecessary sphincter sacrifice.

INTRODUCTION

Lower rectal cancer refers to a tumor located within 5 cm from the anal verge. Management of low rectal cancers is challenging. Sir Ernest Miles[1] was the first to describe the abdomino-perineal resection (APR) in 1908. For nearly a century, this procedure remained the gold standard for rectal cancer. APR was associated with high morbidity and a high recurrence rate[1]. The need for a permanent colostomy following APR prompted surgeons to explore sphincter-preserving procedures that adhere to sound oncological principles. Until 1948, all rectal cancers, regardless of tumor height, were managed using APR. In 1948, Dixon[2] introduced anterior resection (AR) as a surgical technique for rectal cancer aimed at preserving bowel continuity. He published his outcomes on 400 patients, following which AR gradually replaced APR for cancers located in the middle and upper third of the rectum. In 1982, Heald et al[3] introduced the concept of total mesorectal excision (TME), challenging Miles' concept of cylindrical tumor spread, which proposed that lymphatic dissemination occurs in upward, lateral, and downward directions. Heald et al[3] emphasised that the primary pathway for lymphatic spread is upward and confined within the mesorectal envelope. Fain et al[4] and Ravitch[5] popularised the use of stapling devices, which significantly advanced sphincter-preserving surgery (SPS) and reduced the rate of APR. A deeper understanding of margin status, recognizing that a distal resection margin (DRM) of less than 2 cm can be adequate, along with the increased emphasis on the circumferential resection margin (CRM), has enabled surgeons to achieve sphincter preservation more effectively[6,7]. The oncological safety of sphincter preservation surgery is based on the principle that low rectal cancers primarily spread lymphatically in the oral direction within the mesorectum, with distal spread occurring only within a few millimetres. Similarly, newer surgical techniques also resulted in better sphincter preservation[8]. SPS are defined as resections with clear CRM, DRM, and complete TME without performing an APR. Several techniques are now available for sphincter preservation, including low AR (LAR), ultra-low AR (ULAR), intersphincteric resection (ISR), and local excision methods such as transanal endoscopic microsurgery (TEM), transanal minimally invasive surgery (TAMIS), and transanal excision (TAE). Additionally, transanal TME (TaTME) has emerged as an advanced approach for select cases. Advancements in stapling devices, a better understanding of tumor spread, and the recognition of the CRM as a key prognostic factor (over the distal margin) have significantly contributed to an increased rate of sphincter preservation. Additionally, the growing use of neoadjuvant chemoradiotherapy for locally advanced rectal tumors has further enhanced this trend. The current local recurrence rate after SPS ranges from 0%-23%[9]. The local recurrence rate compared to APR for following SPS is not worse compared to APR, as well documented by many studies[10-13]. However, deciding whose sphincter can be preserved without hampering oncological safety is challenging. The decision to proceed with SPS rather than an APR is based on many factors, including response to chemoradiation, adequate margins, the patient’s functional status and comorbidities, sphincter function, and the patient's desire to preserve their sphincter. Early identification of these factors enables surgeons to determine whether sphincter preservation is feasible. This review explores the factors that may predict sphincter-preserving resection without compromising oncological outcomes and quality of life.

MATERIALS AND METHODS

This review studied the various factors predicting the SPS for low rectal cancer. Literature on sphincter preservation surgery for low rectal cancer was reviewed between 2000 and 2024 using PubMed and MEDLINE. We searched for terms like ‘low rectal cancer’, ‘resection’, ‘surgery’, ‘inter-sphincter’, ‘sphincter-saving’, ‘predictive factor’, ‘factors associated with’ and Boolean operators like AND, OR, and NOT. Secondary sources from these publications were manually assessed for relevance. Only English language articles which were relevant to the factors associated with sphincter-sparing surgery in low rectal cancer were included. Case reports were excluded. Study selection was conducted by both the authors (Yajnadatta Sarangi, Ashok Kumar). Any disagreement regarding study selection was resolved by Ashok Kumar. Publications were categorised as patient-related factors, tumor-related factors, imaging, biochemical and molecular markers, tools and technologies, and the preoperative neoadjuvant chemoradiotherapy. The results are discussed in detail.

RESULTS

We have divided the various predictive factors influencing sphincter-sparing surgery into patient-related factors, tumor related factors, surgeon-related and others [the role of neoadjuvant chemoradiotherapy (NACRT), the role of magnetic resonance imaging (MRI), biochemical markers], tools and techniques (Figure 1).

Figure 1  Predictive factors for sphincter preservation in low rectal cancer.

Patient-related factors

Various studies have found that a young age at presentation is associated with a higher rate of sphincter preservation compared to older age[14,15]. The probable cause of this is the old age patient associated with poor sphincter function compared to younger age group patients. Similarly, some studies suggest that females may have a higher sphincter preservation rate than males, possibly due to the greater ease of creating a working space in the female pelvis compared to the male pelvis[16]. While there is no definitive supporting data, it is technically more challenging to operate on the pelvis of an obese male compared to that of a female[17]. There are some studies indicating that a high body mass index (BMI) correlates with a lower rate of sphincter preservation compared to a lower BMI, likely due to the challenges of navigating a narrow pelvis in patients with higher BMI[18,19]. Diefenhardt et al[20] in a post hoc analysis of the CAO/ARO/AIO-04 randomized phase III trial found that obese patients are associated with less SPS compared to non-obese. Further sub analysis found that female patients underwent more SPS compared to males. Meyerhardt et al[21] analysed the results of intergroup trial 0114 and found that obese males are associated with an increased rate of APR. Higher BMI favours intersphincteric dissection rather than stapled anastomosis. In a study by Weiser et al[22], ISR was preferred in patients with high BMI because a narrow pelvis makes it difficult to staple.

Numerous studies have excluded patients with impaired anal function, as well as those with severe preoperative conditions such as cardiac failure, liver cirrhosis, renal dysfunction, respiratory dysfunction, or psychiatric disorders from ISR. Additionally, impaired preoperative sphincter function is linked to unfavourable outcomes following sphincter preservation surgery.

Tumor related factors

Ideal anatomical and tumor factors linked to improved outcomes after SPS include well- or moderately differentiated T1–3 tumors located at least 0.5 to 1.5 cm above the dentate line, regardless of internal anal sphincter (IAS) invasion. Mobile tumors are better predictors of sphincter preservation. Larger tumor size and T4 stage increase the risk of recurrence. Most studies have found that poorly differentiated T4 tumors, fixed tumors on digital rectal examination, external anal sphincter (EAS)/levator ani muscle (LAM) infiltration, and/or untreatable distant metastases are unsuitable for SPS. Rullier et al[23] have described the best guide to SPS based on MRI classification of the pelvis. Types of SPS depend on the distance of the distal end of the tumor from the anorectal junction (ARJ) and the dentate line (DL). The author divided tumors into 4 types. For type 1 tumors located more than 1 cm from the ARJ, ULAR is typically the preferred approach, and coloanal anastomosis can be performed using either a hand-sewn technique or a double-stapling method. For type II, III, and IV tumors, ISR is indicated. Japanese studies further modified the types of ISR into three categories: (1) Total ISR (complete removal of the IAS at the intersphincteric groove); (2) Subtotal ISR (the resection line lies between the DL and the intersphincteric groove); and (3) Partial ISR (the resection is at the level of the dentate[24]. The selection of the distal transection line should be based on the lower border of the tumor to achieve adequate distal clearance (DRM ≥ 1 cm). Table 1[9,22,25-55] summarises the anatomical and pathological tumor characteristics that favour SPS in low rectal cancer.

Table 1 Anatomical and pathological characteristics of the tumor affecting the sphincter-preserving surgery.

Ref.	Sample size	Results
[9]	n = 130	Distal end of tumor within 4 cm from anal verge. T1 to T3 tumor. Well-moderately differentiated adenocarcinoma, performance status ECOG 0-2. No pre operative faecal incontinence. Non fixed tumor. Treatable distant metastases
[22]	n = 148	Distal end within 5 cm from anal verge. No metastasis. No EAS/LAM involvement. No incontinence
[25]	n = 27	T2 and T3 rectal cancer. 0.5 to 1.5 cm above dentate line. Well differentiated. No involvement of EAS or pubo rectalis muscle. Node negative disease
[26]	n = 121	T1-T3 rectal cancer. Well to moderately differentiated. No EAS/LAM involvement. Good sphincter function
[27]	n = 92	Rectal carcinoma located at or below 4.5 cm from the anal verge. Lower edge of the tumor less than 2 cm from the anorectal ring. No EAS/LAM involvement. No metastasis. No pre operative faecal incontinence. Non fixed tumor. All T2 tumor and t3 tumor with IS involvement Underwent NACRT
[28]	n = 65	Lower end of tumor lies within 0.5-2 cm from DL T1–2 tumor. T3 Tumor (above puborectalis sling). Well to moderately differentiated tumor. Patients with possibly distinct invasion of the pelvic floor musculature. Underwent prior NACRT. EAS and levator ani free from tumor. Pre operative incontinence
[29]	n = 90	T1–3 tumor. Lower margin 2-5 cm from anal verge. Absent of EAS/LAM invasion. No pre operative faecal incontinence. T4 tumor only if distal margin adequate and sphincters are free
[30]	n = 278	Distal margin at the DL or 1–2 mm distal to it. T2–3 tumor. Well/moderately differentiated adenocarcinoma. Distal end of tumor within 3 to 6 cm from anal verge. Absent of EAS/LAM invasion. No preoperative faecal incontinence
[31]	n = 122	Medically fit for surgery. Normal sphincter function. Distance between the tumor and the anorectal junction < 2 cm. No EAS/LAM involvement. No signs of disseminated disease
[32]	n = 132	Distal edge of tumor within 1-5 cm from anal verge. No involvement of inter sphincteric groove. No EAS/LA involvement. No metastasis
[33]	n = 40	Within 2 cm from dentate line. T1-2 tumor. Diameter 1-5 cm. Well-differentiated or moderately differentiated tumor. Sufficient anal function demonstrated by digital palpation and sphincter manometry. Absence of distant metastases. Absence of intestinal obstruction. Absence of EAS/LAM involvement
[34]	n = 107	No EAS/LAM involvement. Distal margin of at least 2 cm for T2 or T3 tumors or 1 cm for T1 tumors. Well to moderately differentiated tumor. No incontinence
[35]	n = 47	No pre operative faecal incontinence. The distal tumor margin at the dentate line or, at most, 1 to 2 mm distal to the dentate line. No EAS/LAM involvement. Well-differentiated or moderately differentiated histology. No distant metastases (except for resectable liver metastases). All patients received neo adjuvant chemo radiotherapy therapy
[36]	n = 210	Low rectal cancer. Distal margin should at least 1 cm. No pre operative faecal incontinence. T3/T4 and n+ tumor all received NACRT
[37]	n = 26	Distal end of tumor 1-2 cm from ano-rectal ring. T1-T3 tumor. No Infiltration of EAS and LAM
[38]	n = 43	Lower edge of tumor within 5 cm from anal verge. Well to moderately differentiated. Absence of EAS/LAM invasion. Absence of distant metastases
[39]	n = 1289 (systemic review)	Distal end < 1 cm from ano-rectal ring. No metastasis. No EAS /LAM involvements. Mobile tumor not fixed. No pre operative faecal incontinence
[40]	n = 175	The lower edge of the tumor was less than 2 cm from the anorectal ring or involving anorectal ring. No EAS/LAM involvement. No metastasis. No pre operative faecal incontinence. Non fixed tumor. Underwent NACRT
[41]	n = 60	The inferior border of the tumor located within 5 cm from the anal verge (or 2 cm from the anorectal junction). Absence of synchronous distant metastasis. No EAS/LAM involvement. Fully continent preoperatively
[42]	n = 149	T1 to T3. Lower edge of tumor within 5 cm from anal verge. Well to moderately differentiated tumor. No EAS/LAM involvement. No incontinence pre operatively
[43]	n = 55	Normal pre operative sphincter function; Distance between the tumor and the anorectal junction (upper edge of the surgical anal canal) of less than 2 cm. No involvement of the EAS/LAM. No signs of disseminated disease. Patients having T3, T4, and node positive rectal cancer Underwent NACRT
[44]	n = 77	Lower end of tumor within 2 cm from anorectal ring. No EAS/LAM involvement
[45]	n = 134	Underwent NACRT. No EAS/LAM involvement
[46]	n = 163	Tumor height. Tumor size. Post NACRT T and N stage
[47]	n = 219	Lower border of the tumor was clinically at or within 1 cm above the anorectal ring. Intersphincteric groove was preserved. No EAS/LAM involvement. Elderly patients, obese patients, and those with a poor anal sphincter tone
[48]	n = 60	Low rectal cancer located up to 5 cm from the anal verge. No EAS/LAM involvement
[49]	n = 2125	No EAS/LAM involvement. Well differentiated tumor. No pre-operative faecal incontinence
[50]	n = 18452	Young age, early stage disease, female sex and well differentiated histology
[51]	n = 37	Tumors located at 1.5 cm from the dentate line or 1 cm from the anorectal ring. Pre op Wexner score > 10. No EAS/LAM involvement
[52]	n = 147	Low rectal cancer located up to 4 cm from the anal verge. No EAS/LAM involvement. T3/T4 and node positive tumor. Good response to NACRT
[53]	n = 161	Within 5 cm from the anal verge. Minimally-invasive approach. No previous history of CRC. No evidence of synchronous CRC
[54]	n = 330	Tumor distance 3.3 cm 1.9 cm from anal verge. No EAS/LAM involvement
[55]	n = 434	Tumor distance from the anal verge before and after CRT, the occurrence of clinical T downstaging, post-CRT weight and clinical N stage

CRC: Colorectal cancer; NACRT: Neoadjuvant chemoradiotherapy; EAS/LAM: External anal sphincter/levator ani muscle; ECOG: Eastern Cooperative Oncology Group.

Preoperative factors

Various preoperative factors that determine the SPS are preoperative MRI, Margin status, i.e., DRM and CRM, Biochemical markers, and Response to NACRT.

Role of MRI: MRI accurately predicts the DRM, CRM, sphincter involvement, and the exact distal end of the tumor in rectal cancer staging[56]. MRI accurately predicts the distance of the tumor from the anal verge, which is one of the most important factors to consider when evaluating sphincter preservation surgery. Additionally, MRI accurately predict the integrity of the plane between the mesorectum and the levator ani and the external sphincter below, and the integrity of this plane is another important factor predicting successful outcomes after SPS. The MERCURY II study demonstrated the usefulness of MRI in accurately assessing the low rectal cancer surgical plane or intersphincteric plane, thereby reducing the local recurrence rate[57]. MRI is essential for assessing and analysing the feasibility of ISR after NACRT. By predicting DRM and CRM after NACRT, MRI emerges as the best modality for aiding surgery planning. Post-NACRT, T stage and CRM status are crucial in deciding between ISR and APR. Additionally, MRI accurately identifies patients initially planned for APR who become eligible for ISR after being downstaged by NACRT. Diffusion-weighted imaging (DWI) and the apparent diffusion coefficient (ADC) in post-treatment MRI serve as valuable tools for evaluating tumor response and assisting in tumor prognostication. MERCURY trial demonstrated that both pretreatment and post-treatment MRI staging accurately correlated with disease free survival and recurrence rate. The MERCURY study group found that the MR-tumor regression grading (TRG) criteria accurately correlate with tumor response after NACRT[56]. Good response after NACRT, measured by the amount of fibrosis, can be accurately estimated by MRI and graded as TRG. A good response after NACRT is an important factor for good oncological outcomes after SPS. Krdzalic et al[58] found that post-NACRT MRI accurately predict the sphincter preservation in patients with low rectal cancer, with distance from ARJ playing the most important role in determining the sphincter preservation. Similarly, Kim et al[59] found that post-NACRT, MR CRM involvement accurately predicts the failure of SPS. Popita et al[60] found that diagnostic accuracy of MRI of anal sphincter invasion was 91.3%, with a negative predictive value of 100%. Gu et al[61] established a 3D pelvic model using MRI and spiral computed tomography (CT), finding that distance of > 5 cm from anal verge and a BMI < 25 kg/m² were linked to better SPS outcomes. Conversely, shorter upper pubis to sacrococcyx diameter, sacrococcyx distance, and excessive sacral curvature predicted sphincter preservation failure in some cases. Zhou et al[62] studied the CT pelvimetry and found that the diameter of the upper pubis to coccyx affects the success of SPS for mid-low rectal cancer patients. MRI also helps in deciding whether to go for local excision or TME for early-stage rectal cancer. Presence of mesorectal node, T3 tumor and presence of EMVI are absolute contraindications for local excisions, which are accurately identified by MRI staging. Many studies have shown that MRI sometimes over-stages the T stage of the tumor, artificial intelligence (AI) models have been used with MRI to prevent over-staging of the T stage[63]. Advances imaging techniques to predict sphincter preservation: (1) DWI: It is based on the principle of restricting the diffusion of water molecules in tissue, resulting in high signal intensity in highly cellular tissue and low signal intensity in fibrotic or acellular tissue. It helps in response assessment after NACRT. Response assessment after NACRT can be classified as TRG, where patients with a good response have better outcomes after SPS. ADC quantitative parameter derived from DWI, where low ADC results in high viable tumor cells and low response to NACRT; (2) Magnetisation transfer MRI: This is based on the principle of evaluating macromolecular protein content by using the differences in the magnetisation interaction of free water protons and macromolecularly bound protons[64]. Martens et al[65] found that magnetisation transfer imaging can accurately differentiate good and bad responders after NACRT; (3) Dynamic contrast-enhanced MRI: Dynamic contrast-enhanced imaging techniques based on the principle of tumor vessel function (perfusion, permeability) and extracellular-extravascular space composition. The poorer the vascularity of the tissue, the poorer the response to therapy. So various studies found that it can be used to asses pre-treatment prognostications and response assessment after NACRT. With this imaging, one can predict a good prognostic tumor and plan SPS accordingly[66]; and (4) multiparametric imaging: Multiple imaging techniques can be used to identify favourable prognostic tumors, where SPS can be planned, such as tumor perfusion assessed by perfusion CT and metabolism evaluated by positron emission tomography (PET), which can identify unfavourable biological tumors where SPS can be avoided. However, there is not much literature on this subject and its still evolving. Gu et al[67] studied the DC MRI and PET and found a positive correlation regarding tumor vascularity and metabolic activity. Fischer et al[68] Studied the integrated PET/perfusion CT and found that it correlates positively with tumor response.

Biochemical and molecular markers: As long-term oncological outcomes are the main objective of SPS, Various biomarkers have been studied in the past to predict outcomes of sphincter preservation surgery without local recurrence. Various biomarkers available are neutrophil–lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), plasma fibrinogen-NLR, monocyte–lymphocyte ratio and C-reactive protein (CRP). Partl et al[69] studied pre-treatment NLR, PLR, and CRP values on sphincter preservation in low-lying LARC and found that pre-treatment CRP value was an independent factor determining SPS in patients with low rectal cancer. The high amount of CD8+ T cells post-neoadjuvant therapy is associated with a favourable prognosis[70,71]. Tada et al[72] found that increases in post-NACRT interleukin (IL)-6 levels were linked to poor treatment response. They also observed that TNF-α and IL-6 levels were significantly higher post-treatment in non-responders compared to responders. Post-treatment high carcino-embryonic antigen (CEA) is also associated with poor results after sphincter preservation surgery[73]. Increased CRP expression is linked to cancer cell growth, proliferation, and migration. Additional markers for prognosis include various liquid biopsy techniques like the detection of circulating tumor cells (CTCs), circulating tumor DNA, microRNA, cell-free DNA (cfDNA), extracellular vesicles and exosomes. CTCs in the bloodstream indicate metastatic disease, so SPS should be avoided in these patients. KRAS and BRAF mutation in plasma cfDNA is strongly correlated with poor prognosis, and patients with KRAS and BRAF mutation SPS should be avoided[74]. PDL1 expression is also associated with poor treatment response for low rectal cancer after NACRT and preferably treated with immunotherapy before considering SPS[75]. Patients with deficient mismatch repair or microsatellite instability-high status poorly respond to chemoradiotherapy and should preferably be treated with immunotherapy for proper response[76]. Table 2[77,78] summarises various biochemical factors that predict poor long-term outcomes after sphincter preservation.

Table 2 Various biomarkers predicting outcomes after sphincter preservation surgery[77].

Classification	Markers
Haematological markers[78]	Neutrophil–lymphocyte ratio, preoperative plasma fibrinogen and neutrophil–lymphocyte ratio, platelet-to-lymphocyte ratio, monocytes–lymphocyte ratio
Inflammatory markers[78]	Systemic immune-inflammation index, prognostic nutritional index, systemic inflammation response index, ∆pan-immune-inflammation value, CD8+ cell population, interleukin-6 population, TNF-alpha, CRP level
Molecular markers	MSI, BRAF, KRAS, EGFR status, PI3K AKT pathway, CEA level
Liquid biopsy	Circulating tumor cells, circulating tumor DNA, microRNA, cell-free DNA
Pathologic	Tumor budding, EMVI on MRI

MSI: Microsatellite instability; CEA: Carcinoembryonic antigen; CRP: C-reactive protein; TNF: Tumor necrosis factor; EMVI: Extramural venous invasion; MRI: Magnetic resonance imaging.

Role of NACRT: All patients with low rectal cancer who are candidates for SPS should preferably receive NACRT, as it helps to sterilize both the CRM and DRM while facilitating tumor downsizing. It also aids in reducing tumor deposits, budding, and micro metastases[79].

The most compelling evidence regarding the impact of preoperative chemoradiotherapy on sphincter preservation originates from the German rectal cancer study group[80]. Post-NACRT assessment is crucial in determining whether to proceed with ISR, LAR, or APR. Poor NACRT responders are more suitable for APR than SPS. The recurrence rate multiplied by a factor of 9 when there is a poor response to NACRT compared to when there is a response[81]. Numerous studies have demonstrated favourable oncologic outcomes following tumor downstaging[52]. Retrospective studies show that 30%–89% of patients initially thought to need an APR had SPS after preoperative chemoradiation[82,83]. NACRT is also associated with various post-operative problems like sexual, urinary and faecal disturbances[84-86]. Table 3[52,79,87-95] outlines studies showing the downstaging effects of NACRT.

Table 3 Effect of neoadjuvant chemoradiotherapy on sphincter preservation surgery.

Ref.	Sample size	Results
[52]	n = 461	Induction chemotherapy resulted incomplete pathological response
[79]	n = 256	NACRT leads to downstaging of disease
[87]	n = 1861	Short-term preoperative radiotherapy reduces the risk of local recurrence in patients with rectal cancer who undergo a standardized total mesorectal excision
[88]	n = 88	Pre operative radiation therapy improves sphincter preservation rate
[89]	n = 1861	Radiotherapy improves local control of tumours
[90]	n = 1861	Preoperative radiotherapy leads to sphincter preservation and reduce recurrence rate
[91]	n = 88	Pre operative radiation improves clinical response and sphincter preservations
[92]	n = 09	Neoadjuvant therapy improve sphincter preservation rate
[93]	n = 251	In low lying rectal cancer good response to Preoperative radiation therapy improves sphincter preservation
[94]	n = 32	Consolidated total neo adjuvant therapy leads to sphincter preservations
[95]	n = 920	Addition of chemotherapy to radiotherapy leads to complete pathological response

NACRT: Neo-adjuvant chemoradiotherapy; ISR: Inter-sphincteric resection.

Surgical margin: The key factors in preventing local recurrence after sphincter preservation surgeries are CRM and DRM. With a better understanding of embryological anatomy, it has become clear that the principal lymphatic spread is upward and located within the mesorectal sleeve. The traditional concept of a 5 cm margin was challenged, and it was evident from the works of Williams et al[96] and Pollett et al[7], who advocated a margin of 2 cm. The most important factor determining the possibility of sphincter preservation surgeries is DRM. Sphincter-sparing surgeries carry the potential risk of leaving microscopic tumor cells behind, DRM. Studies indicate that a sufficient DRM can be 1 cm, as opposed to the traditional 2 cm margin[27,97,98]. Many studies have shown that Patients with large bulky tumors or nodal disease without NACRT have a high risk of DRM involvement beyond 1 cm but a low risk beyond 2 cm[99]. The rates of local recurrence and recurrence-free survival were similar regardless of whether the distal margin was more or less than 1 cm. Further studies confirmed that DRM can be reduced to less than 1 cm without compromising oncological safety after NACRT[100-104]. Many studies have shown equivalent survival outcomes after NACRT even with DRM of less than 1 cm[105]. Kwak et al[106] found that even with a 5 mm margin and margin negative on frozen section, it did not hamper the oncological safety of patients after NACRT, and outcomes were noninferior to patients with DRM > 5 mm. Some authors have proposed a cautious approach in which they have advised a 1 cm margin for stage 1 and 2 tumors, and greater than 1 cm for stage 3 tumor[107]. A better understanding of the distal margin has facilitated an increasing number of SPS in patients who were previously managed with APR. Since pathological specimens tend to contract by 50%-60% following formalin fixation, a distal margin of less than 1 cm is considered acceptable, provided the margin remains negative for tumor involvement[8,108]. Similarly, current evidence suggests CRM is the most important predictor of the recurrence and long-term survival[109,110]. The local recurrence rate is 3 to 4 times higher when CRM > 1 cm compared to when CRM is < 1 cm[111-115]. Factors associated with the involvement of CRM are a poor response to NACRT, palpable tumor fixation, etc. Patients with an adequate distal margin of 1 cm after NACRT and a negative CRM can be considered for SPS.

Surgeon as a factor determining SPS: The anatomy of the lower rectum is complex, making the expertise of the treating surgeon crucial to the final outcomes. The ability of the surgeon to perform an oncologically safe surgery with good functional results is of utmost importance. Many studies have found that the rate of APR is significantly higher when compared to an expert colorectal centre[116-118]. Specialised rectal surgery training improved sphincter preservation rates[119-121]. Similarly, surgeons with larger case volume and hospital volume lead to a lower rate of APR[122-124]. Heldenberg et al[125] found that surgery in a specialised colo-rectal unit leads to an increase in sphincter preservation compared to a non-specialised center.

Similarly, ISR is a highly specialised surgery that requires the highest level of expertise in colorectal surgery. Kuo et al[126] in their study found that the learning curve was associated with significant differences in outcomes after ISR. They found that surgical expertise (as < 18 or ≥ 18 laparoscopic ISR) was associated with significantly less operating time and protective stoma creation. They found that the minimum number of experiences in laparoscopic ISR to perform laparoscopic ISR is 19. Due to the complex nature of the surgery involved in UL-LAR and ISR, highly specialised training and a dedicated colorectal surgeon in a high-volume center are necessary to achieve good long-term outcomes[127].

Tools and technologies

Endomechanical devices: The advent of double staple techniques is one of the important factors that caused drastic changes in SPR for low rectal cancer. Stapling has made the life of surgeons in the lower pelvis easier, where working in a narrow space is very difficult. Some studies comparing the rate of APR before and after stapled devices have made it evident that stapling devices improve sphincter preservation rates[128]. Similarly, in a population-based study in England over the period of 1996-2004, the author found a decline in APR rates from 29.4% in 1996-1997 to 21.2% in 2003-2004[129]. Similarly, a population-based study from the USA found that the APR rate declined from 31.8% in 1998 to 19.2% in 2011, with a significant trend change in 2004 at 21.6% (P < 0.001)[130]. From these studies, it is evident that surgical staplers have contributed to a decline in APR rates. Stapling devices also made progress from double-tine stapling to triple-line technology. Gradual development of powered circular staplers resulted in more controlled firing, ease of use, enhanced safety, and reduced incidence of misfire, thereby reducing anastomotic disruption compared to older circular staplers[131,132].

Similarly, multidisciplinary team discussion (MDT) based managements and improvements in the field of NACRT are also important factors that help in sphincter preservation, as described in the above paragraph.

Method of surgical intervention: There are no definitive data suggesting a higher rate of sphincter preservation in low rectal cancer with MIS compared to open surgery. However, robotic surgery is described as having an advantage in various steps of sphincter surgery, such as ISR and ULAR. Some studies found that robotic ISR is associated with a lower conversion rate and less blood loss compared to laparoscopic ISR[133,134]^. Minimally invasive approaches can be particularly useful for patients with a narrow pelvis and obesity who have low rectal cancer. Both open and laparoscopic approaches involve a perineal phase after the completion of the abdominal procedure. In a study by Kim et al[135], a significant number of patients found that ISR could be completed using only the robotic approach without requiring a perineal phase. The robotic platform provides better ergonomics, fewer tremors, improved dexterity, greater degrees of freedom, and an enhanced, stable three-dimensional camera, which are especially crucial when operating in a narrow pelvis. Following NACRT, there is tissue edema and an obscure plane of dissection, which leads to a restricted view that results in straying into the incorrect plane in low rectal cancer. Especially in ISR, the robotic platform provides improved anatomical visualization, which facilitates correct plane identification and, as a result, improves the sphincter preservation rate. Although evidence is sparse regarding the superiority of robotic platforms in the rate of sphincter preservation, there are some retrospective studies that demonstrate the advantages of robotic surgery in sphincter preservation rates. Zhu et al[136] compared robotic and laparoscopic surgery for rectal cancer and found that the robotic platform was associated with a higher number of sphincter preservation compared to laparoscopic surgery. Petropoulou et al[137] in their study also found that a higher rate of SPS in the robotic approach compared to the laparoscopic and open groups. The REAL study group from China in their randomised controlled trial reported a higher number of APRs in the laparoscopic group compared to the robotic group[138]. Ansari et al[139] found that the robotic platform for low rectal cancer had a higher SPS rate compared to laparoscopic and open surgery. Rouanet et al[140] found that the number of patients who underwent coloanal anastomosis were higher compared to the laparoscopic groups after TME, indicating the efficacy of the robotic platform for very low rectal cancer. Gebhardt et al[141] also found similar findings that the robotic platform performed better in very low-lying rectal cancer.

TaTME was developed to overcome technical challenges in laparoscopic TME and is considered advantageous for patients with a narrow pelvis, visceral obesity, or large tumor diameter[142]. The primary reason surgeons adopt TaTME is its ability to clearly define the circumferential and DRM, achieved by placing a purse-string suture at the distal margin at the start of the procedure. TaTME allows precise distal margin assessment from the start, enhancing resection quality, improving outcomes, and reducing APR rates to promote sphincter preservation[143,144]. TaTME can be performed using the transanal approach or via TEM and TAMIS paltforms[145,146]. Additionally, some studies have shown the feasibility of performing TaTME using a robotic platform[147-149]. Several factors that favour the use of TaTME include male gender, locally advanced rectal cancer, tumors located in the distal third of the rectum, a narrow and/or deep pelvis, visceral obesity, prostatic hypertrophy, large tumor diameter, distorted tissue planes resulting from neoadjuvant radiotherapy, and tumors considered challenging to access via the conventional abdominal approach) is regarded as challenging through conventional abdominal approach[150].

Role of AI: AI has already made a deep road into medical sciences. AI can be used to predict SPS in patients with low rectal cancer in various ways. Combining AI models and MRI can accurately predict the possibility of SPS in low rectal cancer. Radiomics can accurately predict the response after NACRT and assist in planning SPS in favourable patients. Jia et al[151] in their meta-analysis found that the radiomic models can accurately predict the effect of NACRT, with sensitivity, specificity, and AUC of 0.82 (95%CI: 0.71-0.90), 0.86 (95%CI: 0.80-0.91), and 0.91 (95%CI: 0.88-0.93), respectively.AI models can be used with MRI, which can help in staging and pretreatment planning. Kim et al[152] constructed two distinct convolutional neural network models to achieve the automated segmentation of each rectum and tumor, using MRI images and were able to accurately differentiate between T2 from T3 stage. Wu et al[153], based on region-based convolutional neural networks (R-CNN) incorporating MRI, were able to accurately predict tumor stage. AI models based on faster R-CNN were able to predict nodal metastasis better than radiologists[154]. Similarly, incorporating an AI-based model into MRI can better and accurate prediction of external sphincter and LAM invasion, which is an absolute contraindication to sphincter-sparing surgery[155]. The use of AI in PET scans has improved the detection of metastasis rate[156]. Similarly, an AI model can be used to make surgical decision-making. Kudo et al[157] studied 3134 patients and developed a machine-learning artificial neural network (ANN) using data on patients' age and sex, as well as tumor size, location, morphology, lymphatic and vascular invasion, and histologic grade. On the validation cohort, the author found that the ANN model outperformed guidelines in identifying patients with T1 cancers who had lymph node metastasis. Su et al[158] proposed an AI model for the risk of recurrence prediction in patients with T1 RC based on the ANN model. Future prospective models can be used to make an AI-based model that can predict whether the sphincter can be preserved. Kuo et al[159] used algorithm based on logistic regression (LR), Gaussian Naïve Bayes, Extreme Gradient Boosting, Gradient Boosting, random forest, decision tree and light gradient boosting machine able to predict ouctomes of SPS in patients with low rectal cancer. Wang et al[160] on post hoc analysis of LASRE randomized control, used various AI models and were able to predict SPS, with the LR and light gradient boosting models outperforming qualitative analysis in independent testing. AI models can assist in intraoperative decision-making by analysing similar case scenarios, assessing tumor margins, and suggesting steps for surgery. Using radiomics and MRI images, AI models can be trained to assist in determining the distal margin, which is the Achilles heel of SPS in low rectal cancer. Baltussen et al[161], using hyperspectral cameras, were able to accurately predict the distal margin. Similar intra-op margin assessment modalities can also used to train AI models to predict accurate distal margins. Echle et al[162] trained deep neural networks to successfully identify MSI status with an AUC greater than 0.85. Cao et al[163] used an integrated AI model—the Ensemble Patch Likelihood Aggregation model—to predict MSI status. AI has been shown to predict the presence of the tumor mutational burden-high and KRAS proto-oncogene[164]. CNN, an algorithm, could predict disease recurrence risk and overall survival. Currently, AI is progressing, and in the future, large datasets can be prospectively studied to develop models applicable for decision-making in diverse patient populations. Additional efforts are required to make algorithms, particularly deep learning algorithms, interpretable to clinicians and to enhance data preprocessing efficiency. By use of AI, many patients can be excluded from being considered for SPS in Lower rectal cancer. Further studies are required to establish the necessary accuracy rates and ensure the efficacy of AI models in predicting sphincter preservation surgery.

Surgical decision-making: radical resection vs local excision

As described above, considering all favourable factors at present, the Rullier classification and Japanese modification, which is based on an MRI-derived and surgeon assessments of the distal margin, are currently being used to determine the planned resection. Figure 2 describes the surgical margins and various resection modalities for low-lying rectal cancer.

Figure 2 Surgical options for low rectal cancer. A: Low anterior resection; B: Ultra-low anterior resection; C: Partial inter-sphincteric resection; D: Subtotal inter-sphincteric resection; E: Total inter-sphincteric resection; F: Abdominoperineal resection. LAR: Low anterior resection; UL-LAR: Ultra-low anterior resection; ISR: Inter-sphincteric resection; APR: Abdominoperineal resection; IS: Internal sphincter; ES: External sphincter; DL: Dentate line; ARJ: Ano-rectal junction.

Factors affecting the local excision of tumor: Due to the increasing use of screening programs, it’s now possible to detect rectal cancer at an early stage. Early-stage rectal cancer, particularly T1 tumors with invasive adenocarcinoma limited to the submucosa and not extending into the muscularis propria (T2), can be treated with radical resection (RR) involving TME or local excision. In properly selected cases, local excision can achieve a cure. Local excision is linked to lower rates of perioperative complications, stoma construction, and mortality than RR[165]. However, some studies have found that local excision in early-stage cancer is associated with higher rates of local recurrence among patients compared to those treated with TME[166]. The GRECCAR 2 trial failed to show the benefit of local excision, as many patients in the local excision group required a completion TME[167]. In Phase 2, the ACOSOG Z6041 trial demonstrated that neoadjuvant chemoradiotherapy followed by local excision in carefully selected patients with clinically staged T2N0 tumors might achieve outcomes comparable to TME[168]. So it is imperative to identify the factors that predict local excision. Accurate determination of the T and N stages is essential for planning local excision prior to surgery. In this regard, T2-weighted high-resolution MRI and endorectal ultrasound (ERUS) complement each other to best select a patient for local excision; however, the ability to reliably distinguish rectal intramural tumor depth (T1 from T2), ERUS scores over MRI[169,170]. It is important to note that distinguishing between clinical T1 and T2 stages can be challenging, and preoperative assessment often does not accurately correlate with the histologic T stage. So, it’s important to identify the proper T stage in pathologic specimens after excision. The incidence of lymph node metastasis ranges from 6% to 14% for T1 tumors, 17% to 23% for T2 tumors, and 49% to 66% for T3 tumors[171]. Therefore, it is important to select the group of patients who will have a favourable oncological outcome after local excision. Assessing patients for high-risk pathologic features—including tumor grade, lymphovascular invasion, perineural invasion, submucosal (SM) depth, and tumor budding—aids in estimating the risk of micro-metastatic nodal disease, even in clinically or radiographically node-negative cases and local recurrence. Those with T1 tumors invading the deepest part of the submucosa (SM3) have a significantly higher rate of lymph node metastases than those with T1 tumors with more superficial invasion (SM1 or SM2)[172]. This evaluation is essential for guiding the decision to perform completion mesorectal oncologic RR following local excision[171,173]. Currently, only T1 tumors with features listed in Table 4 are considered for local excision. But, randomised controlled trial such as ACOSOG Z6041 and GRECCAR 2 trials failed to prove the advantages of LE over RR. NCCN guidelines are currently laid on certain criteria that favour local excision over TME [National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines^®): Rectal cancer v.1.2025].

Table 4 Criteria for local excision in low rectal cancer.

Factors
Smaller tumors (< 3cm)
Occupying < 30% of the rectal lumen circumference
< 8 cm from the anal verge
With invasion limited to the mucosa superficial submucosa (SM1)
Well-to-moderately differentiation
No lymphovascular invasion
No perineural invasion
Low tumor budding

Studies summarising favourable predictive factors for SPS in low rectal cancer

Only a few studies were conducted assessing the various factors that predict successful SPS in low-lying rectal cancer. Table 5[14,15,72,174-182] summarises studies that combine all relevant factors determining the feasibility of SPS in low-lying rectal cancers.

Table 5 Studies on predictive factors for sphincter-preserving surgery in low-lying rectal cancer.

Ref.	Types of study	Sample size	Predictive factors
[14]	Retrospective	540	Younger age. Good performance status. cT1-T2. Higher relative lymphocyte value. Lower CRP value. Longer interval between CRT and surgery
[15]	Retrospective	268	Younger age at diagnosis, proximal location in the rectum, nonfixed tumor, and institution experience
[62]	Retrospective	42	BMI, distance of tumor from anal verge, diameter of upper pubis to coccyx
[174]	Retrospective	230	Cancers within 4 cm of anal verge, surgeon procedure volume, neoadjuvant radiotherapy
[175]	Retrospective	409	CRM
[176]	Retrospective	1020	Preoperative CEA ≥ 10 ng/ml. T4 stage, N stage, low rectal tumor, advanced age, ASA ≥ III, and male sex
[176]	Retrospective	330	Age > 40. Female sex. Well differentiated tumor. cT1-T2. Distance of tumor from anal verge. Total infiltrated circumference. BMI
[177]	Retrospective	47713	Age < 60, female gender, and white race, high procedural volume
[178]	Retrospective	541	Tumor height prior to CRT higher than 4.5 cm, non mucinous or signet ring adenocarcinoma, pathological T stage higher than T3, preoperative CRT
[179]	Retrospective	403	Tumor location, tumor markers, ASA score, T4 stage, lymph node metastasis, distant metastasis
[180]	Metanalysis	3026	Older age especially > 65 years of age, male sex, ASA score ≥ 3, comorbidity, and distant metastasis
[181]	Retrospective	331	Neoadjuvant chemoradiotherapy, cT3 stage, distant metastasis
[182]	Retrospective	179	neoadjuvant chemotherapy, preoperative radiotherapy, mucinous adenocarcinoma, nerve invasion, and tumour height, CEA

CRT: Chemoradiotherapy; ASA: American Society of Anesthesiologists; CRM: Circumferential resection margin; CRP: C-reactive protein; CEA: Carcinoembryonic antigen; BMI: Body mass index.

DISCUSSION

Several clinical biomarkers, radiological, and tumor-related factors have been described to select patients for sphincter preservation in low rectal cancer. However, many newer markers and techniques are evolving. Based on the literature, authors have compiled various factors (Table 6) that may be useful in decision-making for sphincter preservation. Future studies can develop nomograms to predict SPS in patients with low rectal cancer based on these factors. Currently, The Anus Preservation in Low Rectal Adenocarcinoma Based on mismatch repair/microsatellite instability Status study is being conducted to explore the best model for predicting anus preservation in rectal cancer, taking various factors and MMR status into account[183]. AI models can integrate these factors to identify patients for whom the sphincter can be preserved without compromising long-term oncological results.

Table 6 Various prognostic factors favouring sphincter preservation surgery.

Predictive parameter	Factors
Patient related	Young age, low BMI, female sex, no psychological problem, no past history of colorectal cancer, no pre operative faecal incontinence (Wexner score > 10)
Tumor related (Clinical and pathological)	Preferably T1 to T3 tumor, no involvement of inter sphincteric groove, well to moderately differentiated tumor, EAS and levator ani free from tumor, DRM-1 cm, CRM-1 mm, no distant metastasis, node negative disease
Pre-operative (Biomarkers, imaging, neoadjuvant treatment)	MSI-L status, BRAF and KRAS negative, absence of circulating tumour cells, increase in CD8+ T cell cell-free DNA, ct DNA, DRM-1cm, CRM-1 mm in MRI, good response to NACRT
Surgeon factors	Surgeon’s training, specialized colorectal surgeon, high volume colorectal cancer center

CRM: Circumferential resection margin; DRM: Distal resection margin; NACRT: Neo-adjuvant chemoradiotherapy; MSI: Microsatellite instability; BMI: Body mass index.

CONCLUSION

This review summarizes the predictive factors determining sphincter preservation surgery for low rectal cancer. Various factors such as BMI, pre-operative sphincter function, distance from the anal verge, CRM, DRM, EAS/LAM involvement, response to NACRT, and various markers like CEA, IL-6, MMR status, KRAS, and BRAF involvement determine the feasibility of SPS. Newer imaging modalities, radiomics, and circulating tumor markers, along with the application of AI, are a few of the newer tools that can be used to accurately predict the outcomes of SPS in low rectal cancer. There are some well-established factors/predictors in the literature, but many more are likely to emerge in the future. Colorectal surgeons need to understand these factors before contemplating sphincter preservation surgery.