Predictive model for sphincter preservation in lower 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.

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.

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.

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

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.

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.