Proctectomy for the treatment of rectal cancer results in inevitable changes to bowel habits. Symptoms such as fecal incontinence, constipation, and tenesmus are collectively referred to as low anterior resection syndrome (LARS). Among the several risk factors that cause LARS, anastomotic leakage (AL) is a strong risk factor for permanent stoma formation. Therefore, the purpose of this study was to investigate the relationship between the severity of LARS and AL in patients with rectal cancer based on the LARS score and the Memorial Sloan Kettering Cancer Center (MSKCC) defecation symptom questionnaires.
We retrospectively analyzed patients who underwent low anterior resection for rectal cancer since January 2010. Patients who completed the questionnaire were classified into the AL group and control group based on medical and imaging records. Major LARS and MSKCC scores were analyzed as primary endpoints.
Among the 179 patients included in this study, 37 were classified into the AL group. After propensity score matching, there were significant differences in the ratio of major LARS and MSKCC scores of the control group and AL group (ratio of major LARS: 11.1% and 37.8%, P < 0.001; MSKCC score: 67.29±10.4 and 56.49±7.2, respectively, P < 0.001). Univariate and multivariate analyses revealed that AL was an independent factor for major LARS occurrence and MSKCC score.
This study showed that AL was a significant factor in the occurrence of major LARS and defecation symptoms after proctectomy.
Surgical resection is the basic principle of rectal cancer treatment. With advances in surgical techniques, such as total mesorectal excision, chemotherapy, and radiation therapy, survival rates for rectal cancer have gradually increased, with a 5-year survival rate exceeding 70% in Korea [
However, proctectomy involves inevitable changes in bowel habits, which can impede quality of life. After rectal resection, a series of symptoms occur, including fecal incontinence, constipation, tenesmus, urgency, feeling of incomplete emptying, and frequent bowel movement that are collectively referred to as low anterior resection syndrome (LARS) [
Various factors affect the incidence and severity of LARS. Representative risk factors include preoperative radiotherapy, anastomosis near the anal verge, end-to-end anastomosis without a pouch, and anastomotic leakage (AL) [
Several studies have been conducted on AL associated with LAR, and methods to prevent this have also been demonstrated [
Patients who underwent low anterior resection for rectal cancer from January 2010 to September 2019 at Yeungnam University Medical Center in Daegu, Korea were reviewed retrospectively. Low anterior resection was performed by an experienced colorectal surgeon. At the time of investigation, the study was performed on patients who underwent surgery more than 1 year before. The exclusion criteria were (1) permanent or temporary ostomy at the time of investigation, (2) patients who underwent colon resection or small bowel resection of > 100 cm or gastrectomy in addition to low anterior resection, (3) patients with cognitive or mental disabilities who lack the ability to understand the questionnaire and respond properly, and (4) patients who disagree with the study or have lost contact with the study investigators. If patients did not visit the hospital after follow-up was completed, the researchers explained the study details through telephonic conversations, and if patients agreed, they could visit the hospital at the desired time and complete the questionnaire.
The Korean version of the LARS score questionnaire [
In this study, AL is defined as defects in the intestinal wall of the anastomosis site, and determined based on medical and imaging records and classified as follows based on the classification system commonly used in clinical practice [
To minimize the effect of confounders on selection bias, propensity score and nearest-neighbor matching (PSM) analyses were performed. Patients in the AL group were matched on a 1:2 propensity score with patients in the control group according to age, sex, body mass index, tumor location, neoadjuvant treatment, surgical approach, operative method, anastomosis type, and fecal diversion.
Baseline demographics were compared between the AL and control groups. The Student t-test or Mann-Whitney U-test was used for continuous variables; and for categorical variables, a chi-square test or Fisher exact test was used. Univariate analyses were performed to identify factors associated with the LARS and MSKCC total scores by using logistic regression and linear regression analyses. Variables with P-values of < 0.05 in univariate analyses were included in the multivariate analyses. All statistical analyses were considered significant at P < 0.05. Statistical analysis was performed using IBM SPSS Statistics ver. 22.0 (IBM Corp., Armonk, NY, USA).
This study was approved by the Institutional Review Board of Yeungnam University Medical Center (No. YUMC 2020-03-117-007) with the written informed consent from the patients.
A survey including the LARS score and MSKCC defecation symptom questionnaires was conducted between November 2019 and September 2020. A total of 208 patients met the selection criteria. Patients who were scheduled to visit our institution for the treatment or follow-up of rectal cancer answered the questionnaire after the explanation of the researcher. Of the 208 patients, 179 answered the questionnaire (
Among the 179 patients, 23 patients (12.8%) had grade B leakage and 14 (7.8%) had grade C leakage. A total of 37 patients with grade B and C leakage were classified into the AL group and the remaining 142 patients were classified into the control group.
There was no difference in baseline characteristics between the 2 groups (
Before PSM, univariate analysis showed that major LARS was associated with neoadjuvant therapy, tumor stage, and grade B and C AL. After PSM, neoadjuvant therapy, fecal diversion, tumor stage, and grade B and C AL were significant factors with major LARS in the univariate analysis (
The same analysis was conducted to identify the independent factor for the MSKCC score. Before PSM, grade B and C AL were independent factors for MSKCC score in univariate analysis. Sex, tumor location, and grade B and C AL were independent factors for MSKCC in the univariate analysis after PSM (
The LARS score and MSKCC scores have an inverse relation, which forms a significant (P < 0.001) correlation graph (
Our study findings showed that AL and neoadjuvant chemoradiotherapy affected LARS and defecation symptoms in patients with rectal cancer who underwent LAR. These results are comparable to those of previous studies that also evaluated the factor which affect LARS and defecation symptoms [
The exact diagnosis and approach to LARS depend on asking appropriate questions about the patient’s symptoms. According to a recent meta-analysis, due to the lack of a LARS definition, long-term bowel function was not evaluated, and in 65% of studies, a validated questionnaire was not used [
According to several studies, there are a number of factors that worsen LARS, such as radiotherapy, the extent of rectal excision, the creation of a colonic pouch, and AL. In this study, we focused on AL, a deteriorating factor of LARS. Since there are many factors that affect LARS among the risk factors of AL, such as low-lying tumor and preoperative chemoradiation, correction between the leak group and the no-leak group was performed through PSM. Regarding the impact of postoperative AL on defecation symptoms, there are not much available data and a somewhat heterogeneous investigation of symptoms. There are also few studies on the histological approach of AL. Daams et al. [
If neoadjuvant therapy was performed, surgery was performed 6 weeks after the end of neoadjuvant therapy. Therefore, it can be seen that LARS is worsened by ischemia and fibrosis caused by progressive obliterating endarteritis and the late toxicity of radiotherapy. Gastrointestinal tract ulceration causes symptoms such as perforation, fistulization, and peritonitis, and is associated with an extensive area of fibrosis [
Reduced neorectal reservoir volume is considered a major cause of urgency or incontinence. According to several studies, low-lying tumors or anastomoses of < 5 cm from the anal verge are independent risk factors for deteriorated defecation symptoms [
In our study, female patients showed better bowel function than male patients. To date, there have been no studies that have studied the relationship between bowel dysfunction after low anterior resection and sex difference. The result of our study is expected to be due to the anatomical difference of the pelvis, which is related to the difficulty of surgery. Females had a significantly longer pelvic inlet and outlet, while males had a greater pelvic depth [
In addition to loop ileostomy, which is the traditional method of fecal diversion, patients who performed fecal diversion using the FDD [
This study has several limitations. First, it is a nonrandomized study design. Operators must do their best to prevent AL occurrence, and there cannot be a study design that randomizes AL occurrence. Since patients were classified into 2 groups according to the presence or absence of AL, selection bias may occur regarding factors that may cause AL. Thus, the author implemented the PSM method to compensate for the selection bias. For more effective matching, the number of patients should be greater than in this study. Therefore, prospective multicenter research is needed. Second, this is a study based on a survey; since the questionnaire survey is conducted based on the subjective symptoms of the patient, it may be difficult to use it as an objective indicator, and as the survey is mainly conducted on elderly patients, it is difficult to expect accurate memories. Third, the time of the questionnaire survey from surgery was different for each patient. Since LARS shows a trend of improvement from 1 year postoperatively, studies were conducted on patients who underwent operation for more than 1 year, but many studies have shown that symptoms persist for up to 2 years postoperatively. Therefore, it is necessary to investigate defecation symptoms or LARS at several time points, not at 1-time point postoperatively.
In conclusion, this study showed that AL is a risk factor for major LARS and changes in defecation function after low anterior resection and neoadjuvant chemoradiotherapy. Further prospective multicenter studies are needed to confirm the negative prognostic factors of AL and the relationship with major LARS.
No potential conflict of interest relevant to this article was reported.
Flow chart of study patients. LAR, low anterior resection; uLAR, ultra low anterior resection; AL, anastomotic leakage.
Graph of correlation between low anterior resection syndrome (LARS) score and Memorial Sloan Kettering Cancer Center (MSKCC) score. (A) Before propensity score matching (PSM). (B) After PSM.
Comparison of characteristics before and after propensity score matching
Characteristic | Before matching |
After matching |
||||
---|---|---|---|---|---|---|
AL group (n = 37) | Control group (n = 142) | P-value | AL group (n = 37) | Control group (n = 74) | P-value | |
Age (yr) | 0.343 | 0.308 | ||||
≥ 70 | 9 (24.3) | 46 (32.4) | 9 (24.3) | 25 (33.8) | ||
< 70 | 28 (75.7) | 96 (67.6) | 28 (75.7) | 49 (66.2) | ||
Sex | 0.693 | 0.272 | ||||
Male | 25 (67.6) | 91 (64.1) | 25 (67.6) | 42 (56.8) | ||
Female | 12 (32.4) | 51 (35.9) | 12 (32.4) | 32 (43.2) | ||
BMI (kg/m2) | 0.429 | 0.069 | ||||
≤ 25 | 28 (75.7) | 98 (69.0) | 28 (75.7) | 43 (58.1) | ||
> 25 | 9 (24.3) | 44 (31.0) | 9 (24.3) | 31 (41.9) | ||
Time after surgery (yr) | 0.089 | 0.003 | ||||
≤2 | 9 (24.3) | 56 (39.4) | 9 (24.3) | 40 (54.1) | ||
> 2 | 28 (75.7) | 86 (60.6) | 28 (75.7) | 34 (45.9) | ||
Tumor location | 0.737 | 0.608 | ||||
Upper rectum | 11 (29.7) | 52 (36.6) | 11 (29.7) | 29 (39.2) | ||
Mid rectum | 15 (40.5) | 52 (36.6) | 15 (40.5) | 27 (36.5) | ||
Lower rectum | 11 (29.7) | 38 (26.8) | 11 (29.7) | 18 (24.3) | ||
Neoadjuvant therapy | 0.553 | 0.476 | ||||
No | 32 (86.5) | 117 (82.4) | 32 (86.5) | 60 (81.1) | ||
Yes | 5 (13.5) | 25 (17.6) | 5 (13.5) | 14 (18.9) | ||
Surgical approach | 0.414 | 0.419 | ||||
Open | 6 (16.2) | 16 (11.3) | 6 (16.2) | 8 (10.8) | ||
Laparoscopic | 31 (83.8) | 126 (88.7) | 31 (83.8) | 66 (89.2) | ||
Operative method | 0.932 | 0.722 | ||||
LAR | 30 (81.1) | 116 (81.7) | 30 (81.1) | 62 (83.8) | ||
uLAR | 7 (18.9) | 26 (18.3) | 7 (18.9) | 12 (16.2) | ||
Anastomotic type | 0.942 | 1.000 | ||||
Stapled end to end | 34 (91.9) | 131 (92.3) | 34 (91.9) | 68 (91.9) | ||
Handsewn end to end | 3 (8.1) | 11 (7.7) | 3 (8.1) | 6 (8.1) | ||
Fecal diversion | 0.936 | 0.967 | ||||
No | 13 (35.1) | 50 (35.2) | 13 (35.1) | 30 (40.5) | ||
FDD | 11 (31.8) | 46 (32.4) | 11 (31.8) | 23 (31.1) | ||
Loop ileostomy | 13 (35.2) | 46 (32.4) | 13 (35.1) | 21 (28.4) | ||
IMA ligation | 0.697 | 0.773 | ||||
High | 26 (70.3) | 95 (66.9) | 26 (70.3) | 50 (67.6) | ||
Low | 11 (29.7) | 47 (33.1) | 11 (29.7) | 24 (32.4) | ||
Tumor stage | 0.678 | 0.490 | ||||
I | 7 (18.9) | 34 (23.9) | 7 (18.9) | 20 (27.0) | ||
II | 10 (27.0) | 33 (23.2) | 10 (27.0) | 12 (16.2) | ||
III | 17 (45.9) | 54 (38.0) | 17 (45.9) | 31 (41.9) | ||
IV | 3 (8.1) | 21 (14.8) | 3 (8.1) | 11 (14.9) | ||
LARS score | 28.30 ± 6.4 | 14.60 ± 12.6 | < 0.001 | 28.30 ± 6.4 | 15.62 ± 13.0 | < 0.001 |
LARS classification | < 0.001 | < 0.001 | ||||
No | 2 (5.4) | 86 (60.6) | 2 (5.4) | 42 (56.8) | ||
Mild | 21 (56.8) | 38 (26.8) | 21 (56.8) | 22 (29.7) | ||
Major | 14 (37.8) | 18 (12.7) | 14 (37.8) | 10 (13.5) | ||
MSKCC score | 55.24 ± 7.0 | 66.88 ± 9.1 | < 0.001 | 55.24 ± 7.0 | 66.63 ± 8.5 | < 0.001 |
Values are expressed as mean±standard deviation or number (%).
AL, anastomotic leakage; BMI, body mass index; LAR, low anterior resection; uLAR, ultra low anterior resection; FDD, fecal diversion device; IMA, inferior mesenteric artery; LARS, low anterior resection syndrome; MSKCC, Memorial Sloan Kettering Cancer Center.
Univariate analysis of risk factors for major LARS
Factor | Incidence of major LARS (%) | Before matching |
Incidence of major LARS (%) | After matching |
|||||
---|---|---|---|---|---|---|---|---|---|
P-value | Odds ratio | 95% CI | P-value | Odds ratio | 95% CI | ||||
Age (yr) | |||||||||
≤ 70 | 19.4 | 1 | 23.4 | 1 | |||||
> 70 | 16.4 | 0.725 | 0.859 | 0.369–2.002 | 20.6 | 0.746 | 0.850 | 0.317–2.275 | |
Sex | |||||||||
Male | 17.2 | 1 | 23.9 | 1 | |||||
Female | 20.6 | 0.763 | 1.129 | 0.511–2.494 | 20.5 | 0.673 | 0.820 | 0.326–2.063 | |
BMI (kg/m2) | |||||||||
< 25 | 16.7 | 1 | 21.1 | 1 | |||||
≥ 25 | 22.6 | 0.515 | 1.310 | 0.581–2.951 | 25.0 | 0.639 | 1.244 | 0.499–3.107 | |
Time from surgery (yr) | |||||||||
≤2 | 15.4 | 1 | 18.4 | 1 | |||||
>2 | 20.2 | 0.512 | 1.315 | 0.580–2.982 | 25.8 | 0.353 | 1.546 | 0.616–3.879 | |
Tumor location | |||||||||
Upper rectum | 14.3 | 1 | 12.5 | 1 | |||||
Mid & lower rectum | 20.7 | 0.357 | 1.484 | 0.640–3.439 | 28.2 | 0.064 | 2.745 | 0.941–8.005 | |
Neoadjuvant therapy | |||||||||
No | 14.1 | 1 | 17.4 | 1 | |||||
Yes | 40.0 | 0.005 | 3.529 | 1.472–8.459 | 47.4 | 0.007 | 4.275 | 1.497–12.211 | |
Surgical approach | |||||||||
Open | 27.3 | 1 | 42.9 | 1 | |||||
Laparoscopic | 17.2 | 0.225 | 0.529 | 0.189–1.480 | 19.6 | 0.060 | 0.325 | 0.101–1.048 | |
Operative method | |||||||||
LAR | 17.1 | 1 | 19.6 | 1 | |||||
uLAR | 24.2 | 0.581 | 1.303 | 0.509–3.333 | 36.8 | 0.107 | 2.398 | 0.827–6.957 | |
Anastomotic type | |||||||||
Stapled end to end | 17.6 | 1 | 20.6 | 1 | |||||
Handsewn end to end | 28.6 | 0.284 | 1.957 | 0.573–6.687 | 44.4 | 0.115 | 3.068 | 0.761–12.509 | |
Fecal diversion | |||||||||
No | 12.7 | 1 | 9.3 | 1 | |||||
Yes | 21.6 | 0.187 | 1.793 | 0.754–4.268 | 30.9 | 0.012 | 4.356 | 1.379–13.764 | |
IMA ligation | |||||||||
High | 20.7 | 1 | 25.0 | 1 | |||||
Low | 13.8 | 0.326 | 0.647 | 0.271–1.543 | 17.1 | 0.360 | 0.621 | 0.224–1.723 | |
Tumor stage | |||||||||
I & II | 11.9 | 1 | 12.2 | 1 | |||||
III & IV | 24.2 | 0.037 | 2.364 | 1.051–5.315 | 30.6 | 0.025 | 3.167 | 1.153–8.699 | |
Anastomotic leakage | |||||||||
No & grade A | 12.7 | 1 | 13.5 | 1 | |||||
Grade B, C | 40.5 | 0.001 | 4.193 | 1.832–9.598 | 40.5 | 0.002 | 4.364 | 1.713–11.119 |
LARS, low anterior resection syndrome; CI, confidence interval; BMI, body mass index; LAR, low anterior resection; uLAR, ultra low anterior resection; IMA, inferior mesenteric artery.
Multivariate analysis of risk factors for major LARS
Factor | Before matching |
After matching |
||||
---|---|---|---|---|---|---|
P-value | Odds ratio | 95% CI | P-value | Odds ratio | 95% CI | |
Neoadjuvant therapy | ||||||
No | 1 | 1 | ||||
Yes | 0.001 | 4.960 | 1.886–13.042 | 0.026 | 4.235 | 1.189–15.087 |
Fecal diversion | ||||||
No | NA | NA | NA | 1 | ||
Yes | NA | NA | NA | 0.077 | 3.096 | 0.884–10.837 |
Tumor stage | ||||||
I & II | 1 | 1 | ||||
III & IV | 0.079 | 2.195 | 0.914–5.270 | 0.053 | 3.048 | 0.986–9.422 |
Anastomotic leakage | ||||||
No & grade A | 1 | 1 | ||||
Grade B, C | < 0.001 | 6.129 | 2.471–15.200 | 0.001 | 6.396 | 2.110–19.389 |
LARS, low anterior resection syndrome; CI, confidence interval; NA, not applicable.
Univariate analysis of risk factors for MSKCC score
Factor | Before matching |
After matching |
|||||
---|---|---|---|---|---|---|---|
B (β) | P-value | 95% CI for B | B (β) | P-value | 95% CI for B | ||
Age (yr) | |||||||
≤ 70 | |||||||
> 70 | –0.856 (–0.040) | 0.596 | –4.035 to 2.323 | –0.290 (–0.014) | 0.885 | –4.240 to 3.661 | |
Sex | |||||||
Male | |||||||
Female | 2.831 (0.137) | 0.068 | –0.214 to 5.876 | 4.023 (0.205) | 0.031 | 0.379 to 7.666 | |
BMI (kg/m2) | |||||||
< 25 | |||||||
≥ 25 | –1.184 (–0.055) | 0.468 | –4.394 to 2.026 | 0.163 (0.008) | 0.932 | –3.630 to 3.956 | |
Time from surgery (yr) | |||||||
≤2 | |||||||
>2 | –1.815 (–0.088) | 0.240 | –4.855 to 1.225 | –3.258 (–0.169) | 0.077 | –6.873 to 0.357 | |
Tumor location | |||||||
Upper rectum | |||||||
Mid & lower rectum | –2.807 (–0.135) | 0.071 | –5.852 to 0.239 | –4.208 (–0.211) | 0.027 | –7.916 to –0.500 | |
Neoadjuvant therapy | |||||||
No | |||||||
Yes | –1.512 (–0.057) | 0.448 | –5.435 to 2.412 | 0.423 (0.017) | 0.863 | –4.411 to 5.258 | |
Surgical approach | |||||||
Laparoscopic | |||||||
Open | 1.268 (0.084) | 0.263 | –0.959 to 3.496 | 1.560 (0.108) | 0.259 | –1.167 to 4.287 | |
Operative method | |||||||
LAR | |||||||
uLAR | –0.991 (–0.039) | 0.606 | –4.773 to 2.791 | –2.910 (–0.114) | 0.232 | –7.714 to 1.893 | |
Anastomotic type | |||||||
Stapled end to end | |||||||
Handsewn end to end | –2.995 (–0.081) | 0.280 | –8.443 to 2.454 | –4.655 (–0.132) | 0.166 | –11.268 to 1.958 | |
Fecal diversion | |||||||
No | |||||||
Yes | 1.713 (0.083) | 0.271 | –1.350 to 4.775 | 1.019 (0.052) | 0.590 | –2.715 to 4.752 | |
IMA ligation | |||||||
High | |||||||
Low | 1.695 (0.080) | 0.286 | –1.431 to 4.821 | 2.622 (0.127) | 0.184 | –1.266 to 0.650 | |
Tumor stage | |||||||
I & II | |||||||
III & IV | –0.541 (–0.027) | 0.717 | –3.481 to 2.399 | 1.510 (0.078) | 0.415 | –2.146 to 5.167 | |
Anastomotic leakage | |||||||
No & grade A | |||||||
Grade B, C | –11.637 (–0.476) | < 0.001 | –14.824 to –8.450 | –11.385 (–0.559) | < 0.001 | –14.587 to –8.183 |
MSKCC, Memorial Sloan Kettering Cancer Center; CI, confidence interval; BMI, body mass index; LAR, low anterior resection; uLAR, ultra low anterior resection; IMA, inferior mesenteric artery.
B=unstandardized coefficients, β=standardized β-coefficient.
Multivariate analysis of risk factors for MSKCC score
Factor | Before matching |
After matching |
||||
---|---|---|---|---|---|---|
B (β) | P-value | 95% CI for B | B (β) | P-value | 95% CI for B | |
Sex | ||||||
Male | NA | NA | NA | 0.459 to 6.540 | ||
Female | NA | NA | NA | 3.500 (0.178) | 0.024 | |
Tumor location | ||||||
Upper rectum | NA | NA | NA | |||
Mid & lower rectum | NA | NA | NA | –3.764 (–0.188) | 0.018 | –6.858 to –0.670 |
Anastomotic leakage | ||||||
No & grade A | Reference | |||||
Grade B, C | –11.637 (–0.476) | < 0.001 | –14.824 to –8.450 | –10.651 (–0.523) | < 0.001 | –13.784 to –7.517 |
MSKCC, Memorial Sloan Kettering Cancer Center; CI, confidence interval; NA, not applicable.
B=unstandardized coefficients, β=standardized β-coefficient.
Comparison of LARS score and MSKCC score according to fecal diversion method
Factor | Before matching |
After matching |
||||
---|---|---|---|---|---|---|
Loop ileostomy (n = 59) | FDD (n = 57) | P-value | Loop ileostomy (n = 34) | FDD (n = 34) | P-value | |
LARS score | 18.00 ± 12.84 | 17.75 ± 12.67 | 0.918 | 22.65 ± 11.56 | 19.82 ± 13.29 | 0.353 |
MSKCC score | 64.43 ± 10.18 | 65.74 ± 9.04 | 0.464 | 61.86 ± 9.30 | 64.59 ± 9.17 | 0.229 |
Values are presented as mean±standard deviation.
LARS, low anterior resection syndrome; MSKCC, Memorial Sloan Kettering Cancer Center; FDD, fecal diversion device.