Assessment of the risk of permanent stoma after low anterior resection in rectal cancer patients

doi:10.21203/rs.3.rs-32646/v1

Background

One of the most severe complications of low anterior resection is anastomotic leakage (AL). The creation of a loop ileostomy (LI) reduces the frequency of AL requiring surgical intervention, but up to one-third of temporary stomas may never be closed.

The first aim of the study is to perform a retrospective assessment of the impact of LI on the risk of permanent stoma (PS) and symptomatic AL. The second aim of the study is to assess preoperative PS risk factors in patients with LI.

Methods

A total of 286 consecutive patients who underwent low anterior resection were subjected to retrospective analysis. In 101 (35.3%) patients, diverting LI was performed due to low anastomosis, while in the remaining 185 (64.7%) patients, no ileostomy was performed. LIs were reversed after adjuvant treatment. Analyses of the effect of LI on symptomatic AL and PS were performed. Among the potential risk factors for PS, clinical factors and values of selected peripheral blood parameters were analysed.

Results

PS occurred in 37.6% and 21.1% of the patients with LI and without LI, respectively (p <0.01). Symptomatic ALs were significantly more common in patients without LI. In this group, symptomatic ALs occurred in 23.8% of patients, while in the LI group, they occurred in 5% of patients (p <0.001). In the LI group, the only significant risk factor for PS in multivariate analysis was preoperative plasma fibrinogen concentration (OR = 1.008, 97.5% CI 1.003-1.014, p = 0.003).

Conclusions

Protective LI significantly reduces the incidence of symptomatic AL, but a higher risk of PS is observed in this group of patients. The preoperative serum fibrinogen concentration is a risk factor for PS in LI patients and may be a helpful variable in decision models.

Oncology

low anterior resection

rectal cancer

loop ileostomy

permanent stoma

anastomotic leakage

fibrinogen

In rectal cancer surgery, there is a noticeable tendency to widen the indications for sphincter-sparing procedures. The most serious complication of these procedures is anastomotic leakage (AL), the frequency of which in low anterior resections (LAR) can reach up to 30%. [1] Although the effect of loop ileostomy (LI) on reducing the symptomatic AL frequency has been demonstrated, the frequency of permanent stoma (PS) after LAR with LI may exceed 30%, and in elderly patients, this rate can even reach 50%. [2, 3]

In addition, given the possible complications associated with the presence of ileostomy, such as electrolyte disturbances and renal dysfunction, as well as the risk of surgical complications associated with the ileostomy itself and ileostomy closure procedures, it is necessary to define the group of patients who actually benefit from elective diversion. [4, 5, 6] The stoma nonclosure rate is difficult to compare since the authors may or have not have adopted the latest expected time to closure criteria, which ranges from 9 to 36 months. Additionally, various strategies for stoma reversal, including before, during or after adjuvant treatment, have been adopted. The presence of a PS may be caused by both a lack of qualifying for the operation and a consequence of stoma recreation after the closure procedure. [7] The risk factors for PS include advanced age, advanced stage of the disease, narrow radial margin, colorectal AL and adjuvant therapy. [8, 9] However, some of these factors are not known when deciding to create a stoma.

The first aim of the study is to perform a retrospective assessment of the impact of LI on the risk of PS and symptomatic AL. The second aim of the study is to assess preoperative PS risk factors in patients with LI.

Methods

From January 2008 to January 2018, 313 patients with cancer of the lower rectum were operated on at the National Institute of Oncology in Gliwice, and these patients underwent LAR performed with colorectal anastomosis up to 5 cm from the anal verge. In 106 patients, protective LI was performed, and the remaining 207 underwent LAR without LI. Pretreatment staging was performed based on abdominal and pelvic CT, TRUS and/or pelvic MRI, and chest X-ray or CT. All tumours were localized in the lower rectum during the rectal examination. A total of 233 (81.5%) patients underwent neoadjuvant treatment (radiotherapy or radiochemotherapy). In the radiotherapy (RT) group, the patients received a total dose of 25–42 Gy. In the radiochemotherapy group, the patients received one or two cycles of 5-fluorouracil-based chemotherapy followed by pelvic radiotherapy with a total dose of 42–54 Gy. In the group that received neoadjuvant treatment, two subgroups were additionally distinguished based on whether the time from the completion of RT to surgery was < 6 weeks or > = 6 weeks. Before surgery, mechanical bowel preparation was used, with oral neomycin. Intravenous perioperative antibiotic prophylaxis was used. The procedure was performed by laparotomy, and the resection covered the rectum with the mesorectum (TME) up to the level of the pelvic diaphragm, sparing the autonomic nerves. End-to-end anastomosis was performed with a stapler. The integrity of the anastomosis rings was assessed each time, but while no air leak test was performed, as is standard. LI was performed in the right lower abdomen based on the surgeon’s decision in each case. The frequency of LI varied with time. (Fig. 1)

Colorectal AL, according to the International Study Group of Rectal Cancer, was defined as a defect in the integrity of the intestinal wall at the colorectal site that leads to a communication between the intra- and extraluminal compartments, as well as pelvic abscesses in the proximity of the anastomosis [10]. AL was considered symptomatic if accompanied by peritonitis on physical examination and/or intestinal pelvic drainage. Before qualifying for ileostomy reversal, a water-soluble contrast enema was performed each time to exclude asymptomatic AL. During the closure procedure, intestinal anastomosis was performed side to side or end to end depending on the surgeon's preferences. Patients who required adjuvant chemotherapy underwent surgery after adjuvant treatment. Unclosed stoma, regardless of the reason for its creation, was considered a PS after 18 months. In the LI group, 1 (0.9%) death occurred in the postoperative 30-day period. This patient was excluded from further analysis. In addition, 4 patients in whom an ileostomy was created due to technical problems during the formation of the anastomosis were excluded from the LI group. In the group of patients without LI, 2 (1%) deaths occurred in the postoperative 30-day course, and these 2 patients were excluded from further analysis. In this group, similar to the group with LI, 2 patients who had intraoperative technical problems during anastomosis creation were excluded. In addition, to avoid overlooking late leakages, 18 patients without AL, but with an observation period of less than 3 months, were excluded from the non-LI group. Finally, 286 patients were analysed. A total of 101 (35.3%) patients underwent LAR with LI (study group A), while the remaining 185 (64.7%) underwent LAR without LI (control group B). Part of the analysis was performed after using the propensity score matching (PSM) procedure, which aimed to match the study and control groups so that they were composed of similar patients in terms of features such as sex, age, body mass index (BMI), Charlson comorbidity index (CCI), pretreatment clinical stage of the disease, and time from radiotherapy to surgery. The patient characteristics before and after PSM are presented in Table 1.

Table 1

Patients characteristics before and after propensity score matching
		Before propensity score matching				After propensity score matching
		Ileostomy (N = 101)	No ileostomy (N = 185)	Test	p-value	Ileostomy (N = 93)	No ileostomy (N = 93)	Test	p-value
Sex	Female	33.7% (N = 34)	39.5% (N = 73)	chi-square	0.4007	36.6% (N = 34)	35.5% (N = 33)	chi-square	1
Sex	Male	66.3% (N = 67)	60.5% (N = 112)	chi-square	0.4007	63.4% (N = 59)	64.5% (N = 60)	chi-square	1
Age	N	101	185	U Mann-Whitney	0.0708	93	93	U Mann-Whitney	0.6256
	Mean (SD)	61.98 (10.6)	63.96 (10.75)			62.69 (10.26)	62.62 (11.17)
	Median (IQR)	61 (55–71)	65 (58–72)			62 (56–71)	64 (59–69)
	Range	29–83	26–88			29–83	26–88
BMI	N	101	185	U Mann-Whitney	0.3901	93	93	U Mann-Whitney	0.6423
	Mean (SD)	26.86 (4.41)	26.32 (4.33)			26.63 (4.42)	26.89 (4.53)
	Median (IQR)	26 (23.8–29.7)	25,8 (23.4–28.4)			25.8 (23.8–29)	25.7 (23.9–29.9)
	Range	18.4–42.6	14.8–42.5			18.4–42.6	14.8–42.5
CCI	0	69.3% (N = 70)	65.4% (N = 121)	chi-square	0.7288	69.9% (N = 65)	66.7% (N = 62)	Fisher	0.8288
	1–5	23.8% (N = 24)	28.1% (N = 52)			24.7% (N = 23)	25.8% (N = 24)
	> 5	6.9% (N = 7)	6.5% (N = 12)			5.4% (N = 5)	7.5% (N = 7)
Clinical stage	II	29.7% (N = 30)	35.7% (N = 66)	chi-square	0.5922	32.3% (N = 30)	31.2% (N = 29)	Fisher	0.8885
	III	63.4% (N = 64)	57.8% (N = 107)			62.4% (N = 58)	61.3% (N = 57)
	IV	6.9% (N = 7)	6.5% (N = 12)			5.4% (N = 5)	7.5% (N = 7)
RT	no RT	20.8% (N = 21)	17.3% (N = 32)	chi-square	0.0797	21.5% (N = 20)	18.3% (N = 17)	chi-square	0.7094
	Time RT-OPER > 6 weeks	50.5% (N = 51)	40.5% (N = 75)			47.3% (N = 44)	45.2% (N = 42)
	Time RT-OPER < 6 weeks	28.7% (N = 29)	42.2% (N = 78)			31.2% (N = 29)	36.6% (N = 34)
SD- standard deviation, IQR- interquartile range, BMI- body mass index, CCI- Charlson comorbidity index, RT- radiotherapy, Time RT-OPER- time from completion of radiotherapy to operation

Risk factors for PS were assessed in group A. Among the potential risk factors, sex, age, BMI, body surface area (BSA), presence of comorbidities expressed on the CCI scale, coronary artery disease (CAD), diabetes (DM), pretreatment stage of the disease, neoadjuvant treatment, time from completion of radiotherapy to surgery, preoperative values of peripheral blood morphotic elements, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and preoperative fibrinogen plasma concentration (FIBR) were analysed.

Percentage distributions (for variables on a nominal scale) or descriptive statistics, including the mean, median, standard deviation (SD), and first and third quartile values (Q1-Q3), are used to describe patient characteristics, complications, and treatment efficacy on different scales. The nonparametric Mann-Whitney U test was used to compare numerical variables between two groups of observations. Fisher's test or the chi-square test was used to investigate the relationship between two categorical variables. A logistic regression model was constructed by selecting a subset of variables based on univariate analysis, followed by backward stepwise elimination using the Akaike information criterion (AIC). Model coefficients were used to calculate odds ratios, whose values indicate how many times the chance of the investigated event occurring increases with each unit increase in the value of the given predictor variable. An analysis was then performed to clarify whether a fibrinogen-based test could be useful for differentiating patients requiring permanent stoma. For this purpose, a receiver operating characteristic (ROC) curve was plotted, for which the optimal threshold was selected, and the sensitivity and specificity of the method was determined based on this optimal point. The positive predictive value (PPV) and negative predictive value (NPV) of the test were also calculated as thresholds. The area under curve parameter (AUC) was calculated. Its 95% confidence interval was estimated based on DeLong’s method to evaluate the quality of patient stratification based on fibrinogen value.

Based on the estimation of the ROC curve, sensitivity and specificity were calculated for the threshold maximizing both of these values. In addition, the PPV and NPV have also been presented. PPV is defined as the proportion of true positives to the sum of true and false positives. Similarly, the NPV of the test is defined as the proportion of true negatives to the sum of true and false negatives. The ROC curve was created by plotting the sensitivity of the test against 1 – specificity. The area under this curve was measured to obtain the AUC parameter. The values of AUC can range from 0 to 1; in optimal situations, the AUC is maximized. Propensity score matching was performed using the nearest neighbour method without replacement. To prevent poor matches, a tolerance value c (calliper) of 0.05 of the averaged standard deviation of the propensity score distribution was determined in the study and control groups. The level of significance was assumed to be α = 0.05, with statistically significant results for the levels α = 0.01 and α = 0.001 mentioned where appropriate. All calculations were made using the statistical package R version 3.6.0

From January 2008 to January 2018, 313 patients with cancer of the lower rectum were operated on at the National Institute of Oncology in Gliwice, and these patients underwent LAR performed with colorectal anastomosis up to 5 cm from the anal verge. In 106 patients, protective LI was performed, and the remaining 207 underwent LAR without LI. Pretreatment staging was performed based on abdominal and pelvic CT, TRUS and/or pelvic MRI, and chest X-ray or CT. All tumours were localized in the lower rectum during the rectal examination. A total of 233 (81.5%) patients underwent neoadjuvant treatment (radiotherapy or radiochemotherapy). In the radiotherapy (RT) group, the patients received a total dose of 25 - 42 Gy. In the radiochemotherapy group, the patients received one or two cycles of 5-fluorouracil-based chemotherapy followed by pelvic radiotherapy with a total dose of 42 - 54 Gy. In the group that received neoadjuvant treatment, two subgroups were additionally distinguished based on whether the time from the completion of RT to surgery was <6 weeks or > = 6 weeks. Before surgery, mechanical bowel preparation was used, with oral neomycin. Intravenous perioperative antibiotic prophylaxis was used. The procedure was performed by laparotomy, and the resection covered the rectum with the mesorectum (TME) up to the level of the pelvic diaphragm, sparing the autonomic nerves. End-to-end anastomosis was performed with a stapler. The integrity of the anastomosis rings was assessed each time, but while no air leak test was performed, as is standard. LI was performed in the right lower abdomen based on the surgeon’s decision in each case. The frequency of LI varied with time. (Fig. 1)

Colorectal AL, according to the International Study Group of Rectal Cancer, was defined as a defect in the integrity of the intestinal wall at the colorectal site that leads to a communication between the intra- and extraluminal compartments, as well as pelvic abscesses in the proximity of the anastomosis [10]. AL was considered symptomatic if accompanied by peritonitis on physical examination and/or intestinal pelvic drainage. Before qualifying for ileostomy reversal, a water-soluble contrast enema was performed each time to exclude asymptomatic AL. During the closure procedure, intestinal anastomosis was performed side to side or end to end depending on the surgeon's preferences. Patients who required adjuvant chemotherapy underwent surgery after adjuvant treatment. Unclosed stoma, regardless of the reason for its creation, was considered a PS after 18 months. In the LI group, 1 (0.9%) death occurred in the postoperative 30-day period. This patient was excluded from further analysis. In addition, 4 patients in whom an ileostomy was created due to technical problems during the formation of the anastomosis were excluded from the LI group. In the group of patients without LI, 2 (1%) deaths occurred in the postoperative 30-day course, and these 2 patients were excluded from further analysis. In this group, similar to the group with LI, 2 patients who had intraoperative technical problems during anastomosis creation were excluded. In addition, to avoid overlooking late leakages, 18 patients without AL, but with an observation period of less than 3 months, were excluded from the non-LI group. Finally, 286 patients were analysed. A total of 101 (35.3%) patients underwent LAR with LI (study group A), while the remaining 185 (64.7%) underwent LAR without LI (control group B). Part of the analysis was performed after using the propensity score matching (PSM) procedure, which aimed to match the study and control groups so that they were composed of similar patients in terms of features such as sex, age, body mass index (BMI), Charlson comorbidity index (CCI), pretreatment clinical stage of the disease, and time from radiotherapy to surgery. The patient characteristics before and after PSM are presented in Table 1.

Risk factors for PS were assessed in group A. Among the potential risk factors, sex, age, BMI, body surface area (BSA), presence of comorbidities expressed on the CCI scale, coronary artery disease (CAD), diabetes (DM), pretreatment stage of the disease, neoadjuvant treatment, time from completion of radiotherapy to surgery, preoperative values of peripheral blood morphotic elements, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and preoperative fibrinogen plasma concentration (FIBR) were analysed.

Percentage distributions (for variables on a nominal scale) or descriptive statistics, including the mean, median, standard deviation (SD), and first and third quartile values (Q1-Q3), are used to describe patient characteristics, complications, and treatment efficacy on different scales. The nonparametric Mann-Whitney U test was used to compare numerical variables between two groups of observations. Fisher's test or the chi-square test was used to investigate the relationship between two categorical variables. A logistic regression model was constructed by selecting a subset of variables based on univariate analysis, followed by backward stepwise elimination using the Akaike information criterion (AIC). Model coefficients were used to calculate odds ratios, whose values indicate how many times the chance of the investigated event occurring increases with each unit increase in the value of the given predictor variable. An analysis was then performed to clarify whether a fibrinogen-based test could be useful for differentiating patients requiring permanent stoma. For this purpose, a receiver operating characteristic (ROC) curve was plotted, for which the optimal threshold was selected, and the sensitivity and specificity of the method was determined based on this optimal point. The positive predictive value (PPV) and negative predictive value (NPV) of the test were also calculated as thresholds. The area under curve parameter (AUC) was calculated. Its 95% confidence interval was estimated based on DeLong’s method to evaluate the quality of patient stratification based on fibrinogen value.

Based on the estimation of the ROC curve, sensitivity and specificity were calculated for the threshold maximizing both of these values. In addition, the PPV and NPV have also been presented. PPV is defined as the proportion of true positives to the sum of true and false positives. Similarly, the NPV of the test is defined as the proportion of true negatives to the sum of true and false negatives. The ROC curve was created by plotting the sensitivity of the test against 1 – specificity. The area under this curve was measured to obtain the AUC parameter. The values of AUC can range from 0 to 1; in optimal situations, the AUC is maximized. Propensity score matching was performed using the nearest neighbour method without replacement. To prevent poor matches, a tolerance value c (calliper) of 0.05 of the averaged standard deviation of the propensity score distribution was determined in the study and control groups. The level of significance was assumed to be α = 0.05, with statistically significant results for the levels α=0.01 and α=0.001 mentioned where appropriate. All calculations were made using the statistical package R version 3.6.0

The mean follow-up duration in group A was 46 months (median 41 months) and that in group B was 50 months (median 43 months). Symptomatic AL was significantly more common in group B than in group A (p <0.001; Fisher's test). In group B, symptomatic AL occurred in 44/185 (23.8%) patients, while in group A, symptomatic AL occurred in 5/101 (5%) patients. After PSM, symptomatic AL was found in 20.4% and 5.4% of patients in groups B and A, respectively (p <0.01). In group A, in 3 patients with symptomatic AL, the colorectal anastomosis had to be separated, and Hartmann’s procedure was performed. Of the remaining 98 patients, 32 (32.7%) did not qualify for LI closure. The reasons for not qualifying for LI closure in this group of patients are presented in Table 2. Of the 13 patients whose stoma was not closed due to dissemination/progression of the disease, 5 showed synchronous liver metastases. One of these patients underwent simultaneous metastasectomy, while the other four had potentially resectable metastases and planned for delayed resection. Ileostomy was closed in 66 patients. Four (6%) of these patients had postoperative complications considered grade 3B and 1 (1.5%) had grade 4 complications according to Clavien's classification. As a result of the complications, 2 of these patients had a PS. In addition, there was 1 (1.5%) death in the postoperative 30-day period. This case was also classified as PS. The median time from primary surgery to closure of the ileostomy was 8 months (range 2-18 months). In group B, among the patients with symptomatic leakage, in 34 cases, it was necessary to separate the anastomosis and perform Hartmann’s procedure. In the remaining 10 cases, the anastomosis was preserved, and a protective stoma was created, which was then closed in 5 cases. Finally, in group A, PS was found in 38/101 (37.6%) patients, while in group B, PS was found in 39/185 (21.1%) patients (p <0.01; chi-square test). After PSM between the study and control groups, PS was found in 36.6% and 17.2% of cases, respectively (p <0.01; chi-square test).

Assessment of preoperative risk factors for permanent stoma in a group of patients with ileostomy (group A) was performed. The results of univariate analysis are presented in Table 3. Higher values on the CCI scale were associated with the occurrence of PS (p <0.01; Mann-Whitney U test); however, this was because this scale included distant metastases. The pretreatment clinical stage was significantly associated with the risk of permanent stoma (p <0.001; Fisher's test). All patients who had distant metastases at the time of surgery had PS. The mean FIBR was 400.08 mg/dl in the group of patients with permanent stoma and 342.53 mg/dl in the other patients (p <0.01; Mann-Whitney U test). The other analysed risk factors turned out to be insignificant in the univariate analysis. Based on the above analysis and the backward stepwise method, a logistic regression model was constructed. FIBR and CCI values were adopted as potential predictors of the risk of permanent stoma. The latter was discarded during variable selection by backward elimination. All other factors being equal, each unit increase in the FIBR value translated into a 1.008 higher risk of permanent stoma (p <0.01) (Table 4). Due to the abovementioned statistical dependency between variables, the sensitivity and specificity of the hypothetical diagnostic test to assess the risk for permanent stoma based on fibrinogen values were calculated. For this purpose, a ROC curve was plotted to estimate the optimal cut-off fibrinogen value, which was 423.5 mg/dl. At this value, the specificity of the method was 0.935, while its sensitivity was 0.5. The PPV of fibrinogen values for predicting permanent stoma was 82.6%, while the NPV was 75.3%. The AUC was approximately 0.6607. The 95% confidence interval was estimated based on DeLong’s method and ranged from 0.5329 to 0.7884. This means that the AUC value was significantly higher than 0.5. Hence, we can assume that dividing patients based on the estimated cut-off FIBR value is significantly closer to the actual division of patients with permanent stoma than a random division of patients.

LI significantly reduced the risk of symptomatic AL, which confirms the observations of other authors. [11, 12] However, LI was associated with a significantly higher risk of PS than no LI, both before and after PSM. In more than one-third of patients, the temporary LI was not closed after 18 months. Thus, the success of sphincter-saving surgical treatment clearly becomes apparent. One of the reason for this success is probably our adoption of the strategy to reverse ileostomy only after the completion of adjuvant treatment; furthermore, we assumed that the priority is oncological treatment. The optimal time to close the protective ileostomy after LAR and the sequence of proceedings, taking into account possible adjuvant treatment, have not yet been determined. Early (8-13 days) reversal procedures have been shown to be safe in selected patients. [13, 14] However, there are reports that both early (<30 days) and late (> 6 months) stoma closure may be associated with an increased rate of postoperative complications. [15, 16] Despite several reports of good functional and oncological results of stoma reversal during adjuvant chemotherapy, there are no known results of randomized trials to date. [17, 18] It should be considered that the occurrence of postoperative complications when closing the stoma before or during adjuvant chemotherapy may be a reason to discontinue further treatment.

In the assessment of PS risk factors in the group of patients with LI (group A), only preoperative and intraoperative factors were taken into account, since only such factors are useful when making a decision about creating a LI. Postoperative factors described in the literature, such as AL, local recurrence or metachronous dissemination, cannot be used in the decision model. [19, 20, 21] In addition, we did not distinguish between primary (no qualifications for stoma closure) and secondary PS risk factors (complications after reversal procedure), but we searched for factors independent of the aetiology of PS. We have not confirmed the impact of some of the PS risk factors described, such as age or the presence of comorbidities. [22] CCI proved to be an important factor in univariate analysis, but only at >5, which was associated with the presence of synchronous distant metastases. The analysis did not show, however, the impact of specific diseases such as CAD or DM on PS risk. It seems that stage IV patients are not suitable candidates for LAR with LI, even in cases where the metastases are potentially resectable.

The only risk factor for PS in group A in multivariate analysis was preoperative fibrinogen concentration. The obtained predictive values for preoperative fibrinogen concentration are insufficient for this variable to be considered an independent factor in the preoperative assessment of PS risk; however, the obtained positive and negative predictive values of 82.6% and 75.3%, respectively, indicate that he preoperative fibrinogen concentration may be helpful in the decision model.

Fibrinogen is a 340 kDa glycoprotein synthesized in hepatocytes. As a precursor to fibrin, as well as a key proponent in bridging platelets, fibrinogen is an important component of haemostasis. However, it has been shown that a high serum fibrinogen concentration is associated with the development and progression of tumours. Although this phenomenon has not yet been definitively understood, the hypotheses include the ability of fibrinogen to bind growth factors and tumour cells or affect the escalation of the inflammatory response in the tumour environment. These mechanisms lead to the proliferation of cancer cells and increase their invasive potential. [23] Fibrinogen concentration before treatment is a known prognostic factor not only in primary and metastatic colorectal cancer but also in other gastrointestinal cancers. [24, 25] Considering that in our study, the most common reason for stoma non-closure was the spread of cancer, which has also been confirmed by other authors [16, 26], the role of fibrinogen in assessing PS risk is reasonable, although, to the best of our knowledge, no such relationship has previously been demonstrated.

Nonetheless, we have not shown the impact of the pretreatment clinical stage of the disease, other than stage IV, on the risk of PS, although the stage of the disease is an important risk factor for metachronous metastases and survival. [27]

It is important to note the relatively high percentage of patients who did not agree to ileostomy reversal. It should be assumed that these patients were insufficiently informed about the treatment method planned for them or did not understand the information provided. This indicates the need to pay special attention to informing patients about the consequences of creating an LI, including information about the risk of a PS. In some of these patients, although sphincter preservation was technically possible, an abdominoperineal resection or low Hartmann procedure with a permanent colostomy should be considered, as these procedures have a lower risk of postoperative complications. Colostomy itself would be more beneficial than a permanent ileostomy. [28, 29, 30]. When discussing the treatment plan, we need to ensure that the patient understands all the possible consequences of a diverting stoma. It should also be considered that, as demonstrated, patients with a higher education level are more likely to quickly undergo ileostomy closure. [3] In the absence of randomized studies on the impact of ileostomy closure time on long-term oncological results, we prefer to close the ileostomy only after adjuvant treatment. Furthermore, our analysis indicates the significant difficulty in performing a preoperative risk assessment of permanent stoma.

The analysis has the limitations typical of retrospective analyses. The decision to perform an ileostomy was always made subjectively by the surgeon. When analysing the percentage of protective ileostomies performed in the following years, there was a clear trend towards stoma creation. It was not possible to assess the total percentage of ALs, and only symptomatic ALs were detected, because in patients without an ileostomy, radiological examinations with a contrast enema were performed only in cases of suspected AL; additionally, in the ileostomy group, radiological examinations were not performed in 11% of the patients. In our study, the percentage of symptomatic ALs in patients without an ileostomy may be biased since patients with a short observation duration were excluded from the analysis.

Protective LI significantly reduces the incidence of symptomatic AL, but a higher risk of PS is observed in this group of patients. The serum fibrinogen concentration before LAR is a risk factor for PS in LI patients and may be a helpful variable in decision models.

AIC- Akaike information criterionAL- anastomotic leakageAUC- area under the curveBMI- body mass indexCAD- coronary artery diseaseCCI- Charlson comorbidity indexCI- confidence intervalCT- computed tomographyDM- diabetes mellitusFIBR- fibrinogenIQR- interquartile rangeLAR- low anterior resectionLI- loop ileostomyMRI- magnetic resonanse imagingNLR- neutrophil to lymphocyte ratioNPV- negative predictive valueOR- odds ratioPLR- platelet to lymphocyte ratioPPV- positive predictive valuePS- permanent stomaPSM- propensity score matchingROC- receiver operating characteristicRT- radiotherapySD- standard deviationTME- total masorectal excisionTRUS- transrectal ultrasonography

Ethics approval and consent to participate

The study was approved by institutional ethics committee (KB/430 − 53/19)

Consent for publication

Not applicable

Availability of data and materials

All data generated or analysed during this study are included in this published article [and its supplementary information files].

Competing interests

The authors declare that they have no competing interests

Funding

The authors have no financial or material support to disclose

Acknowledgements

Not applicable

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Tab. 1. Patients characteristics before and after propensity score matching

		Before propensity score matching				After propensity score matching
		Ileostomy (N=101)	No ileostomy (N=185)	Test	p-value	Ileostomy (N=93)	No ileostomy (N=93)	Test	p-value
Sex	Female	33.7% (N=34)	39.5% (N=73)	chi-square	0.4007	36.6% (N=34)	35.5% (N=33)	chi-square	1
Sex	Male	66.3% (N=67)	60.5% (N=112)	chi-square	0.4007	63.4% (N=59)	64.5% (N=60)	chi-square	1
Age	N	101	185	U Mann-Whitney	0.0708	93	93	U Mann-Whitney	0.6256
	Mean (SD)	61.98 (10.6)	63.96 (10.75)			62.69 (10.26)	62.62 (11.17)
	Median (IQR)	61 (55 - 71)	65 (58 - 72)			62 (56 - 71)	64 (59 - 69)
	Range	29 - 83	26 - 88			29 - 83	26 - 88
BMI	N	101	185	U Mann-Whitney	0.3901	93	93	U Mann-Whitney	0.6423
	Mean (SD)	26.86 (4.41)	26.32 (4.33)			26.63 (4.42)	26.89 (4.53)
	Median (IQR)	26 (23.8 – 29.7)	25,8 (23.4 – 28.4)			25.8 (23.8 - 29)	25.7 (23.9 – 29.9)
	Range	18.4 – 42.6	14.8 – 42.5			18.4 – 42.6	14.8 – 42.5
CCI	0	69.3% (N=70)	65.4% (N=121)	chi-square	0.7288	69.9% (N=65)	66.7% (N=62)	Fisher	0.8288
	1-5	23.8% (N=24)	28.1% (N=52)			24.7% (N=23)	25.8% (N=24)
	>5	6.9% (N=7)	6.5% (N=12)			5.4% (N=5)	7.5% (N=7)
Clinical stage	II	29.7% (N=30)	35.7% (N=66)	chi-square	0.5922	32.3% (N=30)	31.2% (N=29)	Fisher	0.8885
	III	63.4% (N=64)	57.8% (N=107)			62.4% (N=58)	61.3% (N=57)
	IV	6.9% (N=7)	6.5% (N=12)			5.4% (N=5)	7.5% (N=7)
RT	no RT	20.8% (N=21)	17.3% (N=32)	chi-square	0.0797	21.5% (N=20)	18.3% (N=17)	chi-square	0.7094
	Time RT-OPER >6 weeks	50.5% (N=51)	40.5% (N=75)			47.3% (N=44)	45.2% (N=42)
	Time RT-OPER <6 weeks	28.7% (N=29)	42.2% (N=78)			31.2% (N=29)	36.6% (N=34)

SD- standard deviation, IQR- interquartile range, BMI- body mass index, CCI- Charlson comorbidity index, RT- radiotherapy, Time RT-OPER- time from completion of radiotherapy to operation

Tab.2. Reasons for ileostomy nonclosure

	n	%
Progression of the disease	13	40,6
Patient refusal	6	18,7
Anastomotic leak	5	15,6
Death during the observation	3	9,4
No eligibility for anaesthesia	2	6,3
Local recurrence	2	6,3
Anastomotic stricture	1	3,1
TOTAL	32	100,0

Tab.3. Univariate analysis of preoperative risk factors for permanent stoma in a group of patients with ileostomy (group A)

			Permanent stoma
		Total (N=101)	Yes (N=38)	No (N=63)	Test	p-value
Sex	Female	33.7% (N=34)	21.1% (N=8)	41.3% (N=26)	Chi-square	0.0621
Sex	Male	66.3% (N=67)	78.9% (N=30)	58.7% (N=37)	Chi-square	0.0621
Age	N	101	38	63	U Mann-Whitney	0.5722
	Mean (SD)	61.98 (10.6)	61.61 (10.39)	62.21 (10.81)
	Median (IQR)	61 (55 - 71)	60 (55 – 71.75)	62 (56.5 - 69)
	Range	29 - 83	40 - 82	29 - 83
Age >= 65	Yes	41.6% (N=42)	36.8% (N=14)	44.4% (N=28)	Chi-square	0.5874
Age >= 65	No	58.4% (N=59)	63.2% (N=24)	55.6% (N=35)	Chi-square	0.5874
BMI	N	101	38	63	U Mann-Whitney	0.4241
	Mean (SD)	26.86 (4.41)	26.61 (4.75)	27.02 (4.23)
	Median (IQR)	26 (23.8 – 29.7)	25.75 (23.1 – 29.38)	26.1 (24.2 – 29.75)
	Range	18.4 – 42.6	18.4 – 38.7	19.4 – 42.6
BMI >= 30	Yes	23.8% (N=24)	23.7% (N=9)	23.8% (N=15)	Chi-square	1
BMI >= 30	No	76.2% (N=77)	76.3% (N=29)	76.2% (N=48)	Chi-square	1
BSA	N	101	38	63	U Mann-Whitney	0.3732
	Mean (SD)	1.87 (0.22)	1.9 (0.24)	1.86 (0.21)
	Median (IQR)	1.88 (1.71 – 2.04)	1.9 (1.7 – 2.08)	1.85 (1.72 – 1.99)
	Range	1.32 – 2.42	1.4 – 2.42	1.32 – 2.38
CAD	Yes	6.9% (N=7)	10.5% (N=4)	4.8% (N=3)	Fisher	0.4206
CAD	No	93.1% (N=94)	89.5% (N=34)	95.2% (N=60)	Fisher	0.4206
HA	Yes	37.6% (N=38)	39.5% (N=15)	36.5% (N=23)	Chi-square	0.9314
HA	No	62.4% (N=63)	60.5% (N=23)	63.5% (N=40)	Chi-square	0.9314
DM	Yes	12.9% (N=13)	15.8% (N=6)	11.1% (N=7)	Chi-square	0.7088
DM	No	87.1% (N=88)	84.2% (N=32)	88.9% (N=56)	Chi-square	0.7088
CCI	0	69.3% (N=70)	52.6% (N=20)	79.4% (N=50)	Fisher	<0.001
	1-5	23.8% (N=24)	28.9% (N=11)	20.6% (N=13)
	>5	6.9% (N=7)	18.4% (N=7)	0% (N=0)
Clinical stage	IV	6.9% (N=7)	18.4% (N=7)	0% (N=0)	Fisher	<0.001
Clinical stage	I-III	93.1% (N=94)	81.6% (N=31)	100% (N=63)	Fisher	<0.001
Time RT-OPER	0	20.8% (N=21)	18.4% (N=7)	22.2% (N=14)	Chi-square	0.374
	1	50.5% (N=51)	44.7% (N=17)	54% (N=34)
	2	28.7% (N=29)	36.8% (N=14)	23.8% (N=15)
FIBR	N	100	38	63	U Mann-Whitney	0.0073
	Mean (SD)	364.4 (88,05)	400.08 (116,1)	342.53 (55,93)
	Median (IQR)	351 (301.75 – 419.25)	410.5 (301.5 – 467.75)	341 (303.75 - 375)
	Range	212 - 721	212 - 721	242 - 491
NLR	N	101	38	63	U Mann-Whitney	0.2119
	Mean (SD)	3.88 (2.06)	4.33 (2.45)	3.61 (1.75)
	Median (IQR)	3.3 (2.5 – 5.1)	3.5 (2.6 – 5.8)	3.1 (2.45 – 4.45)
	Range	1 – 12.2	1 – 12.2	1 – 9.9
PLR	N	101	38	63	U Mann-Whitney	0.8499
	Mean (SD)	262.2 (141.13)	269.6 (174.16)	257.73 (118.2)
	Median (IQR)	232.9 (161.9 – 337.9)	244.45 (143.93 – 351.9)	232.9 (164.25 – 335.15)
	Range	49.3 – 918.8	49.3 – 918.8	74.2 – 509.5

SD- standard deviation, IQR- interquartile range, BMI- body mass index, BSA- body Surface area, CAD- coronary artery disease, DM- diabetes, HA- arterial hypertension, CCI- Charlson comorbidity index, Time RT-OPER- time from completion of radiotherapy to operation, FIBR- preoperative plasma fibrinogen concentration [mg/dL], NLR- neutrophil to lymphocyte ratio, PLT- platelet to lymphocyte ratio

Table 4. Logistic regression model explaining risk of getting a permanent stoma in ileostomy patients

	Odds ratio	2.5 %	97.5 %	Pr(>\|z\|)
Intercept	0.029	0.003	0.203	<0.001
FIBR	1.008	1.003	1.014	0.003

FIBR- preoperative plasma fibrinogen concentration [mg/dL]

supplement6.xlsx

Assessment of the risk of permanent stoma after low anterior resection in rectal cancer patients

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Discussion

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