MRI Measurements Predict Major Low Anterior Resection Syndrome in Rectal Cancer Patients

doi:10.21203/rs.3.rs-1419079/v1

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MRI Measurements Predict Major Low Anterior Resection Syndrome in Rectal Cancer Patients

https://doi.org/10.21203/rs.3.rs-1419079/v1

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Purpose: Current low anterior resection syndrome (LARS) score is lagging behind and only based on clinical symptoms patient described. Whether there are preoperative imaging indicators can be used to predict LARS is unknown. We proposed to identify patients with high risk for major LARS by MRI measurements.

Methods: Patients received curative restorative anterior resection (median 75.7 months since surgery) from Sept. 2007 to Sept. 2015 were collected to complete LARS score. MRI measurements associated with LARS were tested, and a multivariate logistic model was conducted for predicting LARS. Receiver operating characteristic curve was used to evaluate the model.

Results: 255 patients (neoadjuvant chemoradiotherapy) and 72 patients (direct surgery) were enrolled. The incidence of major LARS in NCRT group was significantly higher (53.3% vs.34.7%) (P＝0.005).This study showed that the distance between the tumor’s lower edge and anal rectal joint (ARJ)(DTA) was an important factor for major LARS in both groups (P<0.001). In neoadjuvant chemoradiotherapy group, the thickness of ARJ (TARJ), DTA and sex were independent factors for predicting major LARS; ORs were 0.382 (95% CI, 0.198-0.740), 0.653 (95% CI, 0.565-0.756) and 0.935 (95% CI, 0.915-0.955). The AUC of the model was 0.842 (95% CI, 0.794-0.890). In patients with direct surgery, only DTA was independent factor of major LARS, OR was 0.958 (95% CI, 0.930-0.988). The AUC was 0.777 (95% CI: 0.630-0.925).

Conclusions: Baseline MRI measurements have the potential to predict major LARS in rectal cancer, which will benefit the decision making and improve patients’ life quality.

Rectal cancer

low anterior resection syndrome

magnetic resonance imaging

neoadjuvant chemoradiotherapy

anal rectal joint

Low anterior resection syndrome (LARS) score is lagging behind, while there is no recognized indicators for predicting LARS. This study identified MRI feature for predicting LARS and developed a MR-based model.
The distance between the lower edge of tumor and anorectal joint (DTA) was proved an independent factor for predicting major low anterior resection syndrome (LARS) in both neoadjuvant therapy group and direct surgery group. In neoadjuvant therapy group, the thickness of anal rectal joint (TARJ) was also independent factor for predicting major LARS.
Multivariate models were constructed for predicting major LARS, AUC were 0.842 and 0.777 for neoadjuvant therapy group and direct surgery group, respectively.

Following a restorative anterior resection, 70%–90% of rectal cancer patients report bowel dysfunction [1,2]. Low anterior resection syndrome (LARS) has been used to describe a wide array of symptoms after sphincter-preserving rectal surgery, such as difficulty emptying the bowel, faecal urgency, faecal incontinence and so on. One year after surgery, about 30% of patients report bowel dysfunction resolution (no or mild LARS) will not bring major impact on life quality [1,3]. In contrast, over 40% patients become ‘toilet dependent’ and report that bowel dysfunction has a devastating consequence on their work, social and physical functioning as well as global quality of life (major LARS) [4], and this impact is mostly long-term and persistent, resulting to permanent colostomy in the patients with major LARS.

The incidence of LARS is about 70-90% in European and American countries [1], and the proportion of major LARS is about 20-50%; Chinese studies have reported that the incidence of LARS is about 37.4% - 76% [5,6], of which major LARS is 18.7% - 44%; A retrospective study [7] shows that the incidence of LARS is about 35%, and the major LARS is about 18% in Asian population. It can be seen that the occurrence of LARS has great regional differences, which may be related to the race, and the cognitive level of populations also has an impact on the occurrence of LARS.

The mechanism of LARS is complex and the origin of LARS is probably multifactorial [8,9], including: by injury or stretching of a branch of the autonomous nervous system during rectal excision or due to radiation therapy; decreased rectal compliance and capacity of neurological origin secondary to excision, and et al. The influencing factors of LARS reported in the literature include age, gender, operation type, anastomotic level, pTN stage, postoperative complications, rectal reconstruction mode, the application of neoadjuvant and adjuvant chemoradiotherapy, and so on. Most of them are postoperative factors. Whether there are some influencing factors of LARS, which can be identified before the operation, would help to select patients with high risk of LARS in advance, and implement clinical intervention as soon as possible to avoid or reduce the harm of LARS?

The Low Anterior Resection Syndrome (LARS) score [10] was developed on the basis of patient reported symptoms. The LARS score can accurately measure the severity of postoperative bowel dysfunction and it has been proven to correlate well with quality of life. But the current LARS score is lagging behind (postoperative) and only based on the clinical symptoms that patient described. By far, there is no research on LARS prediction focused on medical imaging measurement (CT/MRI/US). MRI is the standard preoperative imaging examination method for rectal cancer. Whether there are sensitive imaging indicators can be used to predict LARS early (preoperative) is an interesting topic.

The purpose of this study was to personalize the preoperative consent process by: (1) identifying the preoperative risk factors for postoperative bowel dysfunction according to the LARS score; (2) developing a predicting model for major LARS that can be useful in clinical practice by offering individualized information for decision-making at the time of patient consent or during preoperative patient discussions.

The study protocol was approved by the Medical Ethics Committee of Peking University Cancer Hospital, and the content was in accordance with Helsinki Declaration

Data and participants

A retrospective cohort study was performed in Beijing Cancer hospital. Eligible patients received follow-up phone calling to complete the LARS score. The inclusion criteria were 1) an anterior resection performed for a diagnosis of rectal adenocarcinoma between 0 and 15 cm from the anal verge, including patients with neoadjuvant chemoradiotherapy and direct surgery; 2) The patients were followed up for more than 3 years. The five problems related to anal function were as follows: exhaust control; fecal retention of loose stools; frequency of defecation; defecation within 1 hour; urgency of defecation; the incidence of diarrhea; 3) with complete baseline MRI examination; 4) with complete clinical information, including age, gender, BMI, TNM stage, the distance between the lower edge of tumor and anal edge, operation method (laparoscopy or laparotomy), postoperative complications, temporary stoma or not. The exclusion criteria were an incomplete cancer resection, recurrence, metastatic disease, intestinal stoma or patients whose bowel continuity had been restored for <12 months, dementia; with pelvic surgery history before; long term use of drugs that may affect intestinal function and anal defecation function (such as lactulose and other drugs that may affect gastrointestinal motility and defecation condition) after anal preservation; (4) lack of complete clinical and pathological materials and follow-up data; (5) postoperative complications (such as rectovaginal fistula, anastomotic leakage, etc.) affect the quality of defecation; (6) patients with mental disorders and other patients who cannot accurately judge and describe their own conditions; (7) if there is a lack of answers in questionnaires, they shall be eliminated.

LARS score questionnaire

The Low Anterior Resection Syndrome (LARS) score was developed on the basis of patient reported symptoms. The LARS score was computed and categorized into 3 groups: no LARS (0–20 points), minor LARS (21–29 points), or major LARS (30–42 points), according to the guidelines [10]. The time of questionnaire survey was from March 2019 to November 2019. The patients were followed up by face-to-face interview or telephone. Before filling in, the questionnaire will be explained to the patients in detail, and the patients or their families will fill in the questionnaire according to the actual situation. Some questionnaires with missing answers were excluded.

MRI scanning and measurement

All MRI examinations were performed with a 3.0-T MR unit (Discovery 750; GE Healthcare, Waukesha, Wis) by using an eight-channel phased-array body coil in the supine position. Without any bowel preparation, patients were injected intramuscularly with 20 mg of scopolamine butylbromide 30 minutes prior to imaging to reduce colonic motility. The rectal MRI protocol included axial, axial oblique, coronal, and sagittal T2-weighted images; transverse T1-weighted images; diffusion-weighted images. DWI images were obtained using single-shot echo-planar imaging with 2b-factors (0 and 1,000s/mm²), and repetition time (TR)= 2800ms, echo time (TE)=70ms, field of view (FOV)=340x340mm, matrix=256x256, thickness=4.0mm, and gap=1.0mm. Apparent diffusion coefficient (ADC) maps were generated automatically and included both b values in a monoexponential decay model. High-resolution T2WI images were obtained using fast recovery fast spin echo with TR=5694ms, TE=110ms, FOV=180x180mm, echo train length=24, matrix=288x256, thickness=3.0mm, and gap= 0.3 mm.

MRI measurements included (Figure 1): the thickness of levator ani (TLA), Anal-rectal joint (ARJ)(TARJ), internal and external anal sphincter complex thickness (TIS and TES), the distance between tumor’s lower edge and ARJ (DTA), the distance between tumor’s lower edge and anal verge (DTV: DTA + anal canal length), anal canal length, anorectal angle, interspinous diameter (ISD).

Neoadjuvant therapy, surgery and follow-up

All patients received preoperative chemoradiotherapy followed by TME. Intensity-modulated radiation therapy (IMRT) was administered using a Varian Rapidarc system (Varian Medical Systems). The IMRT regimen comprised 22 fractions of 2.3Gy (gross tumor volume, GtV) and 1.9Gy (clinical target volume, CtV). A total dose of 50.6Gy (GtV) /41.8Gy (CtV) was administered 5 times per week over a period of 30days [11,12]. The GtV was defined as the volume of the primary tumor including the mesorectum. The CtV was defined as the primary tumor, mesorectal region, presacral region, mesorectal lymph nodes, lateral lymph nodes, internal iliac lymph node chain, and pelvic wall area. Capecitabine treatment was administered concurrently with IMRT at a dose of 825mg/m² orally twice per day. Low-anterior resection (LAR) based on the principle of TME was recommended 8-12 weeks or more after the completion of chemoradiotherapy. The decision of an LAR were discussed through a MDT discussion before surgery and finally made by intraoperative discretion by the senior surgeon. Double-stapling technique was used for all cases, and a safe distal margin of at least 2cm was achieved in most of cases. Creation of a defunctioning ileostomy and placing pelvic drainages were routinely performed. Adjuvant chemotherapy was routinely recommended to the patients. Capecitabine alone, mfolfoX6, or Capeox were prescribed at the discretion of the physician. Patients were followed at 3-month intervals for the first 2 years after treatment and then at 6-month intervals for the next 3 years. Evaluations consisted of physical examination, serum CEA, a complete blood cell count, and blood chemical analysis. Proctoscopy, abdominal ultrasonography, CT scanning of the abdomen and pelvis, chest X-ray/CT were also routinely performed every 6 to 12 months.

Statistical analysis

All analysis was conducted using SPSS (Version 22.0, SPSS Inc, Chicago). A two-tailed P value less than 0.05 indicated statistically significance. Continuous variables were described as means ± standard deviations, categorial variables were described as numbers and proportions. Independent t test and/or chi-square test were used to compare factors between two groups for detecting LARS-associated factors. Multivariate logistic regression was conducted to screen for independent factors for predicting severe LARS, odds ratios were calculated with 95% confidence interval. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic performance for predicting severe LARS; the area under the ROC curve (AUC) with its 95% CI was calculated. The cutoffs were determined using the maximum Youden’s method.

Patents

The study included 327 rectal cancer patients undergoing surgical resection (Figure 2). The mean age was 57.74±33.40 years. There were 255 patients with neoadjuvant therapy and 72 patients without neoadjuvant therapy. The characteristics of patients were summarized in Table 1.

Statistically higher T and N stage was observed in patients without neoadjuvant therapy compared with patients with neoadjuvant therapy (P<0.001 and P=0.01, respectively).

Statistically more major LARS was observed in patients with neoadjuvant therapy compared with patients without neoadjuvant therapy(53.3% vs 34.7%， P=0.005).

There were statistically differences observed in tumor location, TARJ, TLA, DTA, DTV (DTA+ annal canal length) between patients with neoadjuvant therapy and patients without neoadjuvant therapy, with all P <0.001.

Analysis of LARS associated factors

LARS-associated factors were analyzed in patients with neoadjuvant therapy and patients without neoadjuvant therapy, respectively (Table 2,3).

In patients with neoadjuvant therapy, lower tumor location, thinner TARJ and TLA, and shorter DTA were associated with major LARS. Other MR factors, as well as clinical and pathological characteristics were comparable between major LARS and no/minor LARS patients.

In patients without neoadjuvant therapy, thinner TARJ and TES, and shorter DTA and DTV were associated with major LARS. Additionally, major LARS patients showed higher pathology tumor stage than no/minor LARS patients. Other factors, were comparable between major LARS and no/minor LARS patients.

Construction and evaluation of model for predicting LARS

Analysis was conducted in patients with neoadjuvant therapy and patients without neoadjuvant therapy, respectively.

In patients with neoadjuvant therapy, multivariate logistic regression showed that Sex, TARJ and DTA were independent factors for predicting major LARS; ORs were 0.382 (95% CI, 0.198-0.740), 0.653 (95% CI, 0.565-0.756) and 0.935 (95% CI, 0.915-0.955), respectively (Table 4). The model yielded was Y=－0.961×sex－0.426×TARJ－0.068×DTA, demonstrating an AUC of 0.842 (95% CI, 0.794-0.890) (Table 5, Figure 3).

In patients without neoadjuvant therapy, only DTA was independent factor for predicting major LARS, OR was 0.958 (95% CI, 0.930-0.988) (Table 4). The AUC of DTA for predicting major LARS was 0.777 (95% CI: 0.630-0.925) (Table 5,Figure 3).

The present study analyzed the preoperative clinical factors and radiological features to preidict major LARS in mid-low rectal cancer patients. The results showed that the distance between the lower edge of tumor and ARJ (DTA) was an important influencing factor of major LARS in both neoadjuvant therapy group and direct surgery group. In neoadjuvant therapy group, the thickness of ARJ ring (TARJ) was also significantly correlated with the occurrence of major LARS. Few studies used MR imaging to predict LARS before surgery, these findings may add evidence for function preservation of rectal cancers and contribute for making optimal preoperative strategy.

Many rectal cancer patients have different degrees of low anterior resection syndrome (LARS) after sphincter preservation. The emergence of LARS decreased the quality of life and this impact was mostly long-term and persistent [13,14], resulting to permanent colostomy in those who had major LARS. The needs of predicting major LARS before surgery are growing when more sphincter preserving methods were developed like extra-low anastomosis or local excision after tumor downstaging by NCRT, innovative surgical approach like transanal TME, etc.

The anorectal junction (ARJ) is a powerful muscle ring around the anal canal, which is composed of the muscle bundles from superficial and deep part of the external anal sphincter, the longitudinal muscles of the lower rectum, the internal anal sphincter and the puborectalis of levator ani muscle. It plays a very important role in the anal canal expansion and contraction. If ARJ is injured during the operation, it will lead to fecal incontinence. In this study, the univariate and multivariate analysis demonstrated that the thickness of ARJ ring (TARJ) was a risk factor for major LARS. It can be understood that the patients with thinner ARJ ring had lower anal canal constriction pressure and weaker effect on anal canal. Therefore, the probability of major LARS was higher than those with thicker ARJ ring (% vs.%). As far as we know, there was no imaging study focused on LARS prediction, also there was no MRI related parameter measurement for LARS evaluation.

Besides the location of tumor, we also find the thickness of ARJ is a new predictive factor in neoadjuvant chemoradiotherapy patients. Radiotherapy is a well-known risk factor for LARS, which can lead to short-term and long-term colorectal dysfunction after anterior resection of rectal cancer [15-18]. Among the 255 patients in this study, 53.3% of the radiotherapy patients had major LARS, and only 34.7% of patients with direct surgery had major LARS, suggesting that radiotherapy is related to major LARS. The thickness of ARJ ring was associated with major LARS in NCRT group, but not in direct surgery group. Previous studies have shown that radiotherapy will lead to fibrosis of intestinal tract, pelvic wall tissue and pelvic floor muscles, such as levator ani, inner and outer sphincter muscles [19,20]. We boldly speculate that patients with thicker ARJ ring had more reserves of resting pressure after fibrosis formation and lower probability of major LARS. The relationship between the thickness of ARJ, resting pressure of anus the occurrence of major LARS is to be further explored through objective postoperative anal function test and combined analysis.

We observed the incidence of major Lars after LAR was significant higher in neoadjuvant therapy group than in direct surgery group. To improve local control and R0 resection rate, the strategy of NCRT even total neoadjuvant treatment plus prolonged resting time after radiation were emphasized, especially for cases with local or systemic high risk factor like positive MRF or EMVI or T3c/T3d/T4b substages. Another advantage of NCRT is the higher spincter preservation rate obained through tumor downsize and downstaging [21]. However, the combination of NCRT and low anastomosis is the main cause of major LARS, which decrease patients’ quality of life. The predictive factors reported in the present study may contribute to personalized decision making and inform consent before surgery, to avoid intraoperative discretion of low anastomosis which may definitively cause major LARS. Additional prospective of this predictive model is to promote intentional watch and wait. For low rectal cancer patients of low local and systemic risk, who are more radiosensitive and have more expected cCR rate, intensive neoadjuvant treatment rather than the attempt of broadline sphincter preservation is more rational when major LARS can be predicted.

Above all, the incidence of major Lars after LAR is significant higher in neoadjuvant therapy group, compared with direct surgery group. With the increasing popularity of standardized treatment for rectal cancer and the sufficient guarantee of patients' survival, clinicians should pay enough attention to the high incidence of LARS and its impact on patients' quality of life. Early prediction of major LARS is helpful to the individual treatment strategies. This may aid in the surgical decision making process by helping predict functional outcome at no extra cost or in convenience to the patient. The following scenarios may appear, and LARS prediction may assist clinical decision-making: 1. Screening of patients with neoadjuvant radiotherapy, such as male, middle and low rectal cancer, patients with thinner ARJ ring, patients with no special prognostic risk factors (MRF and/or mr-EMVI negative) and patients with high risk of major LARS, the actual benefits of neoadjuvant radiotherapy should be clarified on MDT and unnecessary neoadjuvant radiotherapy should be avoided as far as possible. If neoadjuvant radiotherapy is necessary (MRF and/or mr-EMVI positive), we still need to clarify appropriate surgical procedures by MDT after neoadjuvant therapy, and the informed consent for the expected anal preservation should be more detailed and targeted; 2. For patients with low rectal cancer, who have good response for neoadjuvant radiotherapy, may have reached cCR on MDT, and but with a higher probability of major LARS, “watch and wait” strategy may benefit more and should be fully communicated with patients; 3. For patients with high risk of major LARS, if neoadjuvant radiotherapy and low anterior resection are unavoidable, health education should be strengthened to make patients fully understand LARS. Postoperative rehabilitation treatment, pelvic floor muscle function training and follow-up should be guided.

Limitations: it is worth noting that the pelvic floor muscles are irregular, three-dimensional, and can not be measured simply and accurately at a certain level (coronal, sagittal, or axial). In this study, pelvic floor muscles are measured simply on a certain plane, rather than 3D volume measurement. We believe 3D volume measurements by using AI would be helpful for LARS prediction; We did not analyze the differences among the three groups of no, mild and major LARS, but the difference between no / mild LARS and major LARS, one of the reasons is that the symptoms of patients with mild LARS can be alleviated over time, and will not have a significant impact on the quality of life of patients; Secondly, because the sample is still small, more samples from multi-centers are needed to be analyzed and verified.

Although MRI play an important role in rectal cancer staging and therapy evaluation after neoadjuvant chemoradiotherapy, there are few studies on the measurement of pelvic floor muscles on MRI, and the relationship between these muscles and LARS. This is the first attempt to use MRI predicting the occurrence of major LARS. To our knowledge, there is no previous imaging study on LARS. Our preliminary results suggest that the thickness of the ARJ ring and the distance between the lower edge of the tumor and ARJ measured on MRI can be used to predict major LARS early before surgery and help to make decision at no extra cost or in convenience to the patient. However, prospective assessment of larger numbers of patients is required to evaluate these findings further.

ARJ

Anal rectal joint

DTA

the distance between tumor’s lower edge and ARJ.

DTV

the distance between tumor’s lower edge and anal verge.

ISD

interspinous diameter.

LAR

low anterior resection.

LARS

low anterior resection syndrome

TLA

the thickness of levator ani.

TARJ

the thickness of Anal-rectal joint.

TIS

the thickness of internal anal sphincter complex.

TES

the thickness of external anal sphincter complex.

ROC curve

receiver operating characteristic curve

AUC

area under the curve.

PPV

positive predictive value.

NPV

negative predictive value.

Disclosure

The authors report no conflicts of interest

Funding Declaration

This work was supported by National Natural Science Foundation of China（82071881, 91959116, 81971584)，National Key R&D Program of China(2019YFC0117705), National Science and Technology Major Project for "Significant New Drug Development" (2020zx09201023) , Beijing Hospitals Authority Youth Programme (Code:QML20181103), Beijing excellent talents training project (2018000021469G260), Beijing Hospitals Authority’ Ascent Plan(Code:20191103)

Author contribution

Xiao-Yan Zhang, Liu Xin-Zhi, Ying-Shi Sun and Ai-Wen Wu designed the study; Xiao-Yan Zhang, Xin-Zhi Liu, Lin Wang, Hai-Bin Zhu, Rui-Jia Sun, Zhen Guan, Qiao-Yuan Lu, Wei-Hu Wang and Zhong-Wu Li collected data; Xiao-Yan Zhang, Xin-Zhi Liu , Xiao-Ting Li, Hai-Tao Zhu, Ying-Shi Sun and Ai-Wen Wu analyzed and interpreted the data; Xiao-Yan Zhang and Xin-Zhi Liu drafted the manuscript; all authors reviewed and approved the manuscript.

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Table 1. The characteristics comparison between patients with neoadjuvant chemoradiotherapy and direct surgery

		Treatment
		Surgery directly（n=72）	Neoadjuvant chemoradiotherapy（n=255）	P
Sex	Male	34(47.2)	162(63.5)	0.013
	Female	38(52.8)	93(36.5)
Age		61.73±10.77	56.62±37.32	0.468
Baseline MRI measurments	TLA	3.33±2.68	4.37±1.67	<0.001
	TARJ	9.21±2.42	8.87±2.41	0.386
	TIS	4.35±1.38	4.54±1.29	0.477
	TES	9.59±2.19	9.39±2.04	0.532
	DTA	56.16±28.85	28.06±17.65	<0.001
	DTV	88.55±29.74	59.17±19.11
	Length of Anal canal	32.39±5.23	31.11±5.25	0.123
	Anorectal angle	107.36±16.35	125.47±17.74	<0.001
	ISD	95.22±10.71	96.13±10.64	0.588
Tumor location	<=50mm	10(13.9)	90(35.3)	<0.001
	>50mm	62(86.1)	165(64.7)
pT	T0	1(1.4)	48(18.8)	<0.001
	T1	0(0)	27(10.6)
	T2	6(8.3)	79(31.0)
	T3	65(90.3)	100(39.2)
	T4	0(0)	1(0.4)
pN	0	44(61.1)	201(78.8)	0.01
	1	20(27.8)	42(16.5)
	2	8(11.1)	12(4.7)
Histopathological type	Adenocarsinoma	65(90.3)	237(92.9)	0.757
	(With) mucinous adenocarcinoma	6(8.3)	15(5.9)
	Signet ring cell carcinoma	1(1.4)	3(1.2)
Differentiation	Middle-high	66(91.7)	219(85.9)	0.195
	Low	6(8.3)	36(24.1)
术式	Dixon	72(100)	255(100)
LARS	No/minor	47(65.3)	119(46.7)	0.005
	Major	25(34.7)	136(53.3)
LARS score		21.29±11.31	29.82±9.25

Note: TLA: the thickness of levator ani. TARJ: the thickness of Anal-rectal joint. TIS and TES: the thickness of internal and external anal sphincter complex. DTA: the distance between tumor’s lower edge and ARJ. DTV (DTA + anal canal length): the distance between tumor’s lower edge and anal verge. ISD: interspinous diameter.

Table 2. Comparison of clinical, MRI and pathological parameters between major LARS and no/minor LARS in neoadjuvant chemoradiotherapy group

		LARS
		No/minor（n=119）	Major（n=136）	P
Sex	Male	68(57.1)	94(69.1)	0.047
	Female	51(42.9)	42(30.9)
Age		54.76±11.93	58.26±49.91	0.456
Baseline MRI measurements	TLA	4.77±1.62	4.01±1.64	<0.001
	TARJ	9.92±2.32	7.97±2.10	<0.001
	TIS	4.58±1.31	4.51±1.22	0.713
	TES	9.63±2.01	9.17±2.04	0.07
	DTA	36.24±18.50	20.91±13.29	<0.001
	DTV	67.66±19.90	51.75±14.91	<0.001
	Length of Anal canal	31.42±5.15	30.83±5.33	0.376
	Anorectal angle	127.49±18.04	123.15±17.16	0.053
	ISD	96.45±10.72	95.85±10.60	0.652
Tumor Location	<=50mm	23(19.3)	67(49.3)	<0.001
	>50mm	96(80.7)	69(50.7)
pT	T0	19(16.0)	29(21.3)	0.491
	T1	14(11.8)	13(9.6)
	T2	35(29.4)	44(32.4)
	T3	50(42.0)	50(36.7)
	T4	1(0.8)	0(50.0)
pN	0	92(77.3)	109(80.1)	0.692
	1	22(18.5)	20(14.7)
	2	5(4.2)	7(5.2)
Histopathological type	Adenocarcinoma	115(96.6)	132(97.1)	0.749
	(With) mucinous adenocarcinoma	2(1.7)	3(2.2)
	Signet ring cell carcinoma	2(1.7)	1(0.7)
Differentiation	Middle-high	103(86.6)	116(85.3)	0.773
	Low	16(13.4)	20(14.7)

Table 3. Comparison of clinical, MRI and pathological parameters between major LARS and no/minor LARS in direct surgery group

		LARS
		No/minor（n=47）	Major （n=25）	P
Sex	Male	24(51.7)	14(56.0)	0.629
	Female	23(48.3)	11(44.0)
Age		62.13±10.11	60.60±12.07	0.571
Baseline MRI measurements	TLA	3.60±2.77	2.97±2.47	0.352
	TARJ	6.69±4.95	5.36±4.38	<0.001
	TIS	4.35±1.38	4.35±1.38	0.686
	TES	9.97±2.47	8.84±1.23	0.03
	DTA	65.42±25.97	37.64±25.80	<0.001
	DTV	97.42±27.73	70.78±26.01	0.002
	Length of Anal canal	32.01±5.26	33.14±5.25	0.486
	Anorectal angle	106.36±15.20	109.34±18.80	0.557
	ISD	97.12±10.45	91.44±10.53	0.088
Tumor location	<=50mm	4(8.5)	6(24.0)	0.072
	>50mm	43(81.5)	19(76.0)
pT	T0	0(0)	1(4.0)	0.024
	T2	6(13.0)	0(0)
	T3	40(87.0)	24(96.0)
pN	0	28(60.9)	15(60.0)	0.326
	1	15(32.6)	5(20.0)
	2	2(4.3)	3(12.0)
	3	1(2.2)	2(8.0)
Histopathological type	Adenocarcinoma	41(89.1)	22(88.0)	0.328
	(With) mucinous adenocarcinoma	5(10.9)	2(8.0)
	Signet ring cell carcinoma	0(0)	1(4.0)
Differentiation	Middle-high	43(93.5)	22(88.0)
	Low	3(6.5)	3(12.0)

Table 4. Multivariate logistic regression results

Treatment		B	OR	95%CI	P
Neoadjuvant therapy	Sex(female=0, male=1)	-0.961	0.382	0.198-0.740	0.004
	TARJ	-0.426	0.653	0.565-0.756	<0.001
	DTA	-0.068	0.935	0.915-0.955	<0.001
Direct surgery	DTA	-0.042	0.958	0.930-0.988	0.005

Note: TARJ: the thickness of Anal-rectal joint. DTA: the distance between tumor’s lower edge and ARJ.

Table 5 Diagnostic performance of models for predicting major LARS

Treatment

AUC

Cut off

sensitivity

specificity

PPV

NPV

accuracy

Neoadjuvant therapy

0.842

（0.794-0.890）

-7.70

86.0%

(80.2%-91.7%)

73.1%

(65.1%-81.1%)

78.5%

(72.0%-85.1%)

82.1%

(74.8%-89.4%)

80%

(75.1%-84.5%)

Direct surgery

0.777

(0.607-0.917)

33.2

60%

(40.8%-79.2%)

90.6%

(80.6%-98.2%)

68.2%

(48.7%-87.7%)

80.8%

(70.1%-91.5%)

79.2%

(70.0%-88.6%)

Note: AUC: area under the curve. PPV: positive predictive value. NPV: negative predictive value.

No competing interests reported.

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Editorial decision: Major revision
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MRI Measurements Predict Major Low Anterior Resection Syndrome in Rectal Cancer Patients

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