Introduction

Functional impairments after rectal cancer surgery have been extensively studied [1,2,3], but impairments after sigmoidectomy are still poorly documented, resulting in insufficient and imprecise information to candidates for surgery. Alterations in urinary, sexual, and defecatory function after sigmoid and rectal cancer surgery are interrelated, partly due to the common extramural autonomic innervation of the structures involved in these functions [4]. Sigmoidectomy entails a high risk of injury to the preaortic sympathetic nerves during high ligation of the inferior mesenteric artery (IMA) and to the superior hypogastric plexus during dissection at the level of the sacral promontory [5].

Accepted surgical techniques for the treatment of locally advanced cancer of the sigmoid colon are sigmoidectomy with high or low ligation of the IMA and left hemicolectomy with high ligation of the IMA including the territory of the left colic artery. Standard CME (s-CME) includes a central vascular ligation with removal of the lymphatic tissue surrounding the IMA. However, as the lymphatic system runs parallel to the venous system and a wide and variable part of the path of the inferior mesenteric vein (IMV) through the left mesocolon does not coincide with that of the IMA, s-CME does not include the mesocolon surrounding the IMV. We refer to CME that includes this portion as extended CME (e-CME).

The gold standard treatment for resectable sigmoid cancer is surgery with curative intention, followed by adjuvant chemotherapy in patients with locally advanced tumors [6]. Complete mesocolic excision (CME) and D3 lymphadenectomy aim to remove the mesentery and all lymphatic, vascular, and neural tissue in the tumor’s drainage area to ensure the removal of any involved lymph nodes [7]. Although many publications have addressed the oncological outcomes of CME and D3 lymphadenectomy [7,8,9], little is known about the impact that these procedures may have on the patients’ defecatory and genitourinary function. A multicenter, single-blind clinical trial (CMELL trial) was undertaken to evaluate whether the number of lymph nodes increases in an extended mesocolic excision [8].

The aim of this study was to depict defecatory, urinary, and sexual function after a high-tie sigmoid colon resection and identify risk factors associated with gastrointestinal and urogenital dysfunction in patients included in the CMELL trial.

Methods

Study design and patients

Data were collected within the single-blind multicenter randomized controlled trial comparing e-CME vs. s-CME for sigmoid colon cancer. The current study was nested within this population but designed to investigate patients’ functionality and risk factors associated with gastrointestinal and urogenital dysfunction.

Between October 2017 and August 2019, all consecutive patients aged ≥ 18 years with histologically confirmed adenocarcinoma of the sigmoid colon, including endoscopically unresectable dysplasia adenomas expected to undergo R0 resection, were randomized to e-CME or s-CME. The trial methodology has been described in detail in the original trial publication [8].

In the s-CME group, only the lymphofatty tissue adjacent to the IMA was extracted, and in the e-CME group, in addition to the extraction of the lymphofatty tissue adjacent to the IMA, the lymphofatty tissue surrounding the IMV to the end of the left colic artery was dissected after high ligation of the IMV[8].

Randomization and masking

Patients were randomly assigned to undergo s-CME or e-CME in a 1:1 ratio using a random sequence generator, with block randomization by the center. Random allocations were sequentially numbered in sealed opaque envelopes, which were opened at the beginning of surgery. Patients were blinded to the assigned group until the end of the study.

Study procedures

Surgical procedures for sigmoid colon cancer resection allocated in the s-CME or e-CME group were described in detail previously [8].

Outcome measures

The primary endpoints were to describe defecatory, urinary, and sexual function after high-tie sigmoid colon resection. The secondary outcome was to identify risk factors associated with gastrointestinal and urogenital dysfunction in patients included in the CMELL trial.

Instruments to measure defecatory, urinary, and sexual function

Patients completed four questionnaires at three time points: before surgery (baseline), 1 month after surgery, and 12 months after surgery.

To assess defecatory function, we used two questionnaires: the COREFO (COloREctal Functional Outcome) questionnaire [10], which comprises 27 questions in five categories (defecation frequency, incontinence, social impact, stool-related aspects, and use of medication), and the Low Anterior Resection Syndrome (LARS) questionnaire [11], which comprises five questions (one about each of the following: gas incontinence, incontinence of liquid stool, frequency of bowel movements, clustering of stools, and urgency).

To evaluate the urinary function, we used the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) to assess the severity of urinary incontinence and its impact on the quality of life; possible scores range from 2 to 20 [12].

To evaluate the male erectile function, we used the International Index of Erectile Function (IIEF-5) [13], which evaluates five domains (erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction), classifying erectile dysfunction as severe (IIEF-5 = 5–7), moderate (IIEF-5 = 8–11), mild-to-moderate (IIEF-5 = 12–16), mild (IIEF-5 = 17–21), or absent (IIEF-5 = 22–25). Although erectile dysfunction is usually defined as IIEF-5 ≤ 21[14], because of the advanced age of our patients, we redefined erectile dysfunction as IIEF-5 ≤ 11 (moderate or severe erectile dysfunction).

To evaluate the female sexual function, we used the Female Sexual Functional Index (FSFI), which comprises 19 questions measuring 6 domains (desire, arousal, lubrication, orgasm, global satisfaction, and pain) [15]. We categorized female sexual function into four groups: severe sexual dysfunction (FSFI = 0–10), moderate sexual dysfunction (FSFI = 11–16), mild sexual dysfunction (FSFI = 17–25), and no sexual dysfunction (FSFI = 26–30); FSFI < 26.55 is commonly accepted as sexual dysfunction.

Predictive variables

We explored the following predictive variables: lymphadenectomy (e-CME or s-CME); age; body mass index (BMI); physical status according to the American Society of Anesthesiologists (ASA) score, dichotomized into I + II or III + IV; diabetes mellitus (no or yes); vein section (no or yes); pT; pN; and adjuvant therapy.

Sample size calculation

Formal power calculation was not undertaken as the original study was designed to investigate whether the number of lymph nodes increases in extended mesocolic excision. Despite functional results were provided as a secondary outcome in the main study, patient functionality was not evaluated in deep. Furthermore, factors associated with functionality at 1 year and surgical recovery were also not assessed previously.

Statistical analysis

We followed the intention-to-treat principle for all analyses. Continuous variables are expressed as medians and interquartile ranges or ranges, as appropriate. Categorical variables are expressed as frequencies and relative frequencies. To compare groups, we used Student’s t-test or the Mann–Whitney U test for continuous variables and the chi-square or Fisher’s exact test for categorical variables.

To identify risk factors associated with defecatory, urinary, and sexual dysfunction 1 year after surgery and with the recovery of defecatory, urogenital, and sexual function 1 year after surgery, we used multivariate linear regression.

Statistical significance was set at p ≤ 0.05. All variables with p ≤ 0.100 in the univariate analyses were included in the multivariate analyses. We used SPSS v. 20.0 (SPSS Inc, Chicago, IL, USA) for all analyses.

Ethical considerations

This study was conducted in accordance with the principles of the Declaration of Helsinki and “good clinical practice” guidelines. The study was registered as NCT03107650 at ClinicalTrials.gov, and the protocol was approved by each participating center’s ethics committee. We followed the Consolidated Standards of Reporting Trials (CONSORT) Guidelines in reporting our findings. All patients provided written informed consent before surgery and before randomization. Patients retained the right to withdraw from the study at any time; patients could be excluded if an exclusion criterion appeared during follow-up.

Results

Patients and baseline characteristics

Seventy-nine patients [45 men and 34 women; 39 from the s-CME arm and 40 from the e-CME arm] were recruited into the original trial. Figure 1 is a flowchart detailing the inclusion of patients in the functional study. Table 1 summarizes the demographic, clinical, surgical, and postoperative characteristics of the patients who completed questionnaires at baseline and 12 months after surgery. There were no significant differences between the two treatment groups in patient characteristics, surgical variables, or pathological outcomes.

Fig. 1
figure 1

Flow diagram of the study

Full size image
Table 1 Patient demographics, clinical, surgical, and morbidity variables
Full size table

A total of 232 questionnaires were collected across the three points of time (baseline, 1 month after surgery, and 12 months after surgery).

Defecatory function

In the entire sample, the median COREFO score was 6.5 (IQR, 0.9‒11.1) before surgery, 8.3 (IQR, 3.9‒13.9) 1 month after surgery, and 5.5 (IQR, 2.8‒10.2) 12 months after surgery.

The median LARS score was 5 (IQR, 0‒20) before surgery, 15 (IQR, 3.3‒27.8) 1 month after surgery, and 11 (IQR, 0‒23) 12 months after surgery (Table 2).

Table 2 Questionnaire assessments of defecatory, urinary, and sexual function at different time points
Full size table

The defecatory function was similar between the two treatment groups at baseline, at 1 month, and at 12 months. The median difference between baseline and 12-month scores was similar for the two groups. One month after surgery, 25.0% of patients had minor LARS and 17.2% had major LARS; the rates of LARS were similar between treatment arms (p = 0.529). Twelve months after surgery, 15.2% of patients had minor LARS and 12.7% had major LARS; the rates of LARS were similar between treatment arms (23.1% in s-CME vs. 32.5% in e-CME, p = 0.548) (Table 2).

In the univariate regression analysis to identify factors associated with bowel function 1 year after surgery, only positive nodal stage was significant with COREFO scores (β = 0.24, p = 0.032), although there was a trend toward significance for adjuvant chemotherapy (β = 0.20, p = 0.084). However, in the multivariate regression analysis, none of the variables remained significant. No significant associations were observed between any factors and LARS scores (Table 3).

Table 3 Factors associated with defecatory, urinary, and sexual function 12 months after surgery
Full size table

In the univariate regression analysis to identify factors associated with the recovery of defecatory function 1 year after surgery, only diabetes was significantly associated with the difference in COREFO scores (β = 0.24, p = 0.032); this factor remained significant in the multivariate analysis (β = 0.24, p = 0.033). The regression analyses found no significant associations between any factor and the difference in LARS scores (Table 4).

Table 4 Differences between total scores on questionnaires assessing defecatory, urinary, and sexual function administered before and 12 months after surgery for sigmoid cancer
Full size table

Urinary function

In the entire sample, urinary function was similar at all time points. The median ICIQ-SF score was 2 (IQR, 2‒5) before surgery, 2 (IQR, 2‒3) 1 month after surgery, and 2 (IQR, 2‒3) 1 year after surgery; the median difference between scores on baseline and 12-month assessments was 0 (IQR, 0‒0) (Table 2).

Postsurgical urinary function in men

One year after surgery, the ICIQ-SF identified urinary dysfunction in 10 (22.2%) men. Median ICIQ-SF scores 1 month after surgery were similar in the two treatment arms [2 (IQR, 2‒2.5) in s-CME and 2 (IQR, 2‒3) in e-CME, p = 0.596]; however, scores 12 months after surgery were significantly different between arms [2 (IQR, 2‒2) in s-CME and 2 (IQR, 2‒6.8) in e-CME, p = 0.026].

In the univariate regression analysis, only e-CME was significantly associated with ICIQ-SF scores 12 months after surgery (β = 0.33, p = 0.026); we found no significant associations between ICIQ-SF scores at this time point and age, BMI ≥ 30 kg/m2, diabetes mellitus, IMV section, tumor or nodal pathology stage, or adjuvant treatment (Table 3).

In the univariate regression analysis to identify factors associated with the recovery of male urinary function 1 year after surgery, only e-CME was significantly associated (β = 0.31, p = 0.039); however, after adjustment in the multivariate analysis, this factor did not remain significant (Table 4).

Postsurgical urinary function in women

One year after surgery, the ICIQ-SF identified urinary dysfunction in 10 (29.4%).

The regression analyses found no significant associations between demographic, clinical, or surgical variables and women’s ICIQ-SF scores 12 months after surgery (Table 3).

In the univariate regression analysis to identify factors associated with the recovery of female urinary function 1 year after surgery, only diabetes mellitus was significant in the univariate analysis (β =  − 0.43, p = 0.011); this factor remained significant in the multivariate analysis (β =  − 0.37, p = 0.039) (Table 4).

Sexual function

Erectile function in men

Median IIEF-5 scores were 18.5 (IQR, 15.8‒21.3) at baseline, 15 (IQR, 8.5‒19.5) 1 month after surgery, and 13 (IQR, 5.3‒18.8) 1 year after surgery (Table 2). One month after surgery, 7 of 21 (33.3%) men had erectile dysfunction; no differences were observed between treatment arms. One year after surgery, 14 of 32 (43.8%) men had moderate-to-severe erectile dysfunction; this proportion was greater in s-CME (60.0%) than in e-CME (29.4%), although differences in median IIEF-5 scores did not reach statistical.

The only risk factor associated with an IIEF score 1 year after surgery was age (β: − 0.38, p = 0.010, in both the univariate and multivariate analyses). Men with erectile dysfunction 1 year after surgery were older than those without erectile dysfunction at this time point [72 (IQR, 67‒74) years vs. 62.5 (IQR, 59.5‒69) years, respectively, p = 0.010] (Table 3).

The difference between median IIEF scores at baseline and 1 year after surgery was greater in the s-CME group [− 7 (IQR, − 15.5‒0.5) vs. − 3 (IQR, − 6‒0) in the e-CME group, p = 0.046]. In the regression analyses to identify factors associated with the recovery of erectile function 1 year after surgery, only the treatment arm was associated with erectile function recovery (β = 0.38, p = 0.046, on both the univariate and multivariate analyses) (Table 4).

Sexual function in women

Median FSFI scores were 27.1 (IQR, 23‒30) at baseline, 5.8 (IQR, 2‒30.2) 1 month after surgery, and 28.3 (IQR, 23.9‒31.2) 1 year after surgery (Table 2). The median difference in scores between baseline and 12 months after surgery was 0.9 (IQR, − 2.9‒3.1).

Median baseline sexual function was similar in the two treatment arms. Of the 11 women who were sexually active before surgery, 8 (73%) were sexually active 1 year after surgery.

In the regression analyses to identify factors associated with sexual function 1 year after surgery, only age was significant (in the univariate analysis β: − 0.59, p = 0.001; in the multivariate analysis β: − 0.54, p = 0.002) (Table 3).

The regression analyses found no significant associations between any factor and the difference in FSFI scores at baseline and 1 year after surgery (Table 4).

Discussion

The current study explored the impact of high-tie sigmoidectomy with s-CME and e-CME for sigmoid colon cancer on defecatory and genitourinary function. Regardless of the extent of lymphadenectomy, sigmoid resection with high ligation had an impact on defecatory and genitourinary function. One year after surgery, 15.2% of patients had minor LARS and 12.7% had major LARS; 22.2% of the men and 29.4% of the women had urinary dysfunction; and 43.8% of the men and 27.3% of the women had sexual dysfunction. Changes in defecatory, urinary, and sexual function after colon cancer surgery are often underestimated and underreported [16]. Our findings underline the importance of taking into account the changes that sigmoid resection has on many patients’ defecatory and genitourinary functions.

In men, extending lymphadenectomy to include the IMV territory (e-CME) resulted in higher rates of urinary dysfunction 1 year after surgery. However, after adjustment in the multivariate analysis, this factor did not remain significant. In women, e-CME was not associated with urinary dysfunction or worse recovery of urinary function at 1 year of surgery.

Remarkably, 1 year after surgery, 43.8% of men had moderate-to-severe erectile dysfunction and 27.3% of the women who were sexually active before surgery had not resumed sexual activity. In both sexes, age was the only risk factor associated with sexual dysfunction 1 year after surgery, and e-CME was not associated with worse recovery of sexual function. However, given the high median age of our sample (71 years in men and 56 years in women), in interpreting our findings, it is important to consider that declines in sexual interest correlate with age and that age-related health problems have a negative impact on sexual desire [17]. Moreover, genitourinary dysfunction manifests as mostly subjective symptoms that are susceptible to evaluation bias when measured with questionnaire-based interviews. Despite strong evidence for deteriorated sexual function in colon cancer survivors of both sexes [8, 18, 19], it is important to remember that multiple factors can influence sexual dysfunction [20]. Finally, a lack of data from women, possibly related to a reluctance to respond to questions about their sexuality, makes it difficult to reach firm conclusions [18, 20].

The main cause of genitourinary dysfunction after colorectal surgery seems to be injuries to the hypogastric nerves and/or to the sacral splanchnic nerve [21,22,23]. Damage to the hypogastric plexus during para-aortic dissection and high ligation of the IMA can result in defecatory and/or genitourinary dysfunction. However, current recommendations regarding CME for cancer of the sigmoid colon reflect the relative lack of information about its effects on defecatory, urinary, and sexual function.

Defecatory function after colon surgery depends on preoperative function, possible nerve damage during surgery, and mechanical changes in the rectum. Up to 41% of patients have minor or major LARS after sigmoid resection for cancer [16, 24]. In our study, only 23.1% of the patients in the s-CME group and 32.5% of those in the e-CME group developed LARS; there were no significant differences between groups at any time point.

The high rates of defecatory and genitourinary dysfunction in both treatment arms of our trial are probably due, at least, in part, to using a high tie in all patients. The oncological benefits of the high tie are controversial. In a randomized study of 331 patients in 2018, Fujii et al. [25] found no differences between high tie and low tie in the rate of anastomotic dehiscence, survival, or local recurrence. Moreover, an observational study including 999 patients found that increasing the number of lymph nodes dissected had no benefit in overall survival or recurrence [26].

Limitations

This was an exploratory study with a small number of patients and with no formal power calculation. Additionally, due to the logistics of questionnaire collection, there were some missing data, mostly in the 1-month postoperative time point, highlighting the difficulty of collecting questionnaires for research. However, there was good-quality data collection at the different study time points.

We did not collect information about whether the surgeon damaged the hypogastric plexus during lymphadenectomy; collecting this information would have allowed us to stratify analyses about functional outcomes and would probably have improved our interpretation of the results. Moreover, we did not use questionnaires to assess ejaculatory function, the International Prostate Symptom Score to assess male urinary function, or other measures that might also have provided useful information.

Nevertheless, the data are useful exploratory results that justify and guide further larger studies to investigate the trend, which were identified in this study.

Conclusions

High tie of the IMA during sigmoidectomy is associated with a high rate of defecatory and genitourinary dysfunction. In both sexes, the sexual function at 1 year after surgery was associated with age. Further studies are needed to investigate the impact of lymphadenectomy and its effects on urinary and sexual function in patients with sigmoid cancer.