Does intestinal anastomosis in resection of colon cancer have a significant impact onto early postoperative outcome and long-term survival?

Statistics

Data management and statistical analyses were performed with the statistical program SPSS (version 21; SPSS Systems; Chicago/IL, USA). Continuous variables such as times and magnitudes are described by the usual measures of mean and standard deviation as well as minimum, lower quartile, median, upper quartile, and maximum. Categorical variables are represented by their absolute and relative frequencies. In addition, the data were examined by survival analysis means using the Kaplan–Meier test, and the respective event probabilities are represented by a Kaplan–Meier curve.

Intergroup differences in survival were compared by the log-rank test. Furthermore, the median survival time and corresponding 95 % confidence interval were calculated. Cox regression was used to analyze the survival data. To reject the null hypothesis, a p-value <0.05 was considered statistically significant.

Furthermore, a matched-pair analysis was applied to ensure comparability between the two groups. In particular, a prospensity-score matched-pair analysis was used to select patients from one group (patients with anastomosis) with regard to certain characteristics and the same patients from another group (patients without anastomosis). The characteristics were sex, age, risk factors, tumor node metastasis stage, and urgency (elective vs. emergency).

Basic data

From 2010 to 2016, data from a total of 14,466 patients were documented (mean age, 72.8 [range, 22–96] years; sex ratio, m:f=7,696:6,770). From this group, 717 patients (4.96 %) were included in a matched-pair analysis. The majority of these patients underwent elective surgery (n=12,620 patients; 87.2 %) regardless of whether a bowel anastomosis or an ostomy was created. In emergency surgery, a bowel anastomosis was possible in a large proportion (n=1,332 patients [72.1 %]). In contrast, 514 patients (27.9 %) who had undergone emergency surgery received an ostomy. An ostomy had to be created even less frequently in patients who had undergone planned surgery (n=366 [2.5 %]; Figure 1).

Figure 1:

Relative proportions of patients with different operation techniques and urgency.

Early postoperative outcomes

Long-term oncological outcomes

Tumor stage

The most important factors influencing long-term survival were age, resection status, and tumor stage (according to TNM and UICC). The more advanced the tumor growth according to its classification, the lower the long-term survival (Figure 2). The median survival time of patients with UICC stage IV cancer was 16.4 months. After 60 months, 79.0 % of the UICC-stage I patients were still alive vs. 65.9 % of those with UICC stage II, 57.7 % of those with UICC stage III, and 13.7 % of those with UICC stage IV (Table 4).

Figure 2:

Long-term survival depending on UICC-stage.

Table 4:

Significant difference – long-term survival of different UICC-stages.

Significant differences – UICC		UICC I	UICC II	UICC III	UICC IV
No anastomosis	UICC I		0.394	0.491	0.057
	UICC II	0.394		0.913	0.000
	UICC III	0.491	0.913		0.000
	UICC IV	0.057	0.000	0.000
Anastomosis	UICC I		0.576	0.043	0.000
	UICC II	0.576		0.002	0.000
	UICC III	0.043	0.002		0.002
	UICC IV	0.000	0.000	0.002

Surgical technique

Comparison of surgical techniques revealed large differences. In patients with ostomy, the median survival time was only 25.7 months. In patients with an anastomosis, the median survival time was longer than the observation period of 60 months. The difference in survival time according to surgical technique was more than 3 years. Regarding the 5-yr-overall survival rate, 59.1 % of the patients with anastomosis were alive after 60 months vs. only 31.5 % without anastomosis, showing a statistically significant difference (Figure 3). In addition, the considerable postoperative mortality in patients with restored intestinal continuity, i.e., without anastomosis, is striking (Table 5).

Figure 3:

Long-term survival depending on surgical technique.

Table 5:

Significant difference – long-term survival of different urgencies.

Significant differences – urgency		Elective	Emergency
No anastomosis	Elective		0.954
	Urgency	0.954
Anastomosis	Elective		0.150
	Urgency	0.150

Operative urgency

Urgency also plays a major role in survival. The median survival time was 29.9 months in patients who had undergone emergency operation or urgent surgery. The 5-yr-survival rate was 60.1 % for elective surgery vs. 37.7 % for urgent surgery.

Accordingly, patients with the same tumor stage, age, and risk factors had a better chance of survival if they had undergone elective surgery or intestinal anastomosis or were elderly (Table 6, Figure 4).

Table 6:

Significant difference – long-term survival of different surgical techniques.

Significant differences – surgical technique	Anastomosis	No anastomosis
Anastomosis		0.18
No anastomosis	0.18

Figure 4:

Long-term survival depending on urgency.

Factors influencing long-term survival (Table 7)

In summary, the following negative factors influencing survival were identified: older age, several risk factors, advanced tumor growth or higher tumor stage (pT, pN, M1, and not reached R0 status [each p=0.000]), no anastomosis (p=0.011), male sex (p=0.001), and emergency surgery (p=0.000).

Multivariate analysis revealed that older patients (p=0.000) and those with distant metastases benefit more from ostomy than those in the same age group or with a given M1 status, in whom an intestinal anastomosis was attempted (p=0.016) (Table 8A and B). The remaining patients significantly benefited from an anastomosis.

Operative aspects and methodological study considerations

To consider these influencing factors and results independently, the formation of matched pairs and the multivariate analysis were crucial. Matched-pairs analysis with respect to pT, pN, R, and M status; UICC stage; grading; risk factors; age; sex; BMI; and colon CA location (forming a “statistical twin group”) allowed the comparison of patients surgically resected for colon CA:

1. with vs. without intestinal anastomosis (as well as)

2. on an elective vs. emergency basis

for determination of the effects of surgical technique and urgency on early postoperative (rather surgical) results and long-term (rather oncological) prognosis.

Early postoperative outcome

The association of intraoperative and postoperative complications with increased postoperative mortality is in line with findings of current studies. In a multicenter observational study, Marusch et al. [10] found that patients who died postoperatively suffered significantly more frequently from general and specific postoperative complications. The same conclusion was also reached in the prospective study of Clauer et al. The major factors influencing overall survival included age, UICC stage, R status, lymph node involvement, cardiovascular disease, and the occurrence of surgery-specific complications [11]. The association of general and surgery-specific complications with certain pre-existing conditions has been demonstrated by various authors. For example, Legler [12] confirmed the association between preoperative concomitant diseases and general as well as surgical complications. In addition, almost all patients who died postoperatively had a concomitant disease. These results are in line with those of current studies. Kirchhoff et al. [9] and Alves et al. [13] also reported an association between postoperative complications and worse pre-existing condition (as measured by “American Society of Anesthesiologists” score). Advanced age also appears to be a significant factor influencing the occurrence of complications [9, 13, 14]. The present study demonstrated the associations between preoperative risk factors and postoperative complications and between complication rate and mortality.

Another important factor influencing the development of complications is the intervention’s urgency. Various studies have shown that emergency interventions (due to ileus, intestinal perforation, etc.) are associated with an increased risk of postoperative complications [15, 16]. The anastomotic insufficiency rate in Legler’s study was 5.4 % for elective surgery vs. 21 % for emergency surgery [12]. In this regard, the current study’s findings support those in the literature. Due to the high complication rate in urgent colon resections, ostomy creation may be considered in these situations. Meyer et al. [17] concluded in a prospective study that this was a good way to perform an emergency colon resection. In particular, this appeared to be a favorable option in cases of ileus or bowel perforation, as it was associated with lower mortality than other radical colon resections. Here, the study results differ. Although emergency procedures are generally associated with more complications than elective procedures, patients in emergency settings also appear to benefit from anastomosis creation vs. discontinuity maintenance (no anastomosis creation), which is longer and more prone to complications. In addition, ostomy creation is advantageous in palliative situations since the postoperative mortality rate is lower in such cases [18].

An interesting further question would be, on the one hand, which complications lead to death and how often. On the other hand, the causes of death of patients without postoperative complications could be analyzed in more detail.

Long-term oncological outcome

The Kaplan–Meier curves for surgical technique and urgency showed significant differences in survival time in the matched-pair analysis, although not with major differences. One reason for this could be the matched-pair analysis itself: Since the “twin groups” differed in only one characteristic (anastomosis vs. none or emergency vs. elective), many patients with a very good perioperative condition and few or no risk factors were excluded because they are rarely treated with ostomy creation. It stands to reason that postoperative mortality rates are high in both types of surgery, as these are patients with poorer preoperative general conditions. Nevertheless, the differences in surgical techniques and urgency are statistically significant (p=0.00). Accordingly, patients with the same tumor stage, age, and risk factors have a better chance of survival if they are operated on electively or with intestinal anastomosis based on the risk profile assessed as acceptable; in other words, the creation of an intestinal anastomosis and elective surgery are prognostically favorable factors in colon CA resection. The multivariable analysis confirmed this with the exception of older patients and those with distant metastases.

This finding is in line with those of De Simone et al. [19]. In a retrospective study, the authors found that patients with a more disadvantageous general condition (measured semiquantitatively by “American Society of Anesthesiologists” score) and acute symptoms benefit from a shorter operating time due to ostomy creation and avoidance of the more complication-prone anastomosis placement. Ansaloni et al. recommended that patients at high surgical risk should be treated with ostomy placement to avoid anastomotic insufficiency [20] or prevent it completely. Wong et al. confirmed that ostomy creation is performed more frequently in the elderly [21], but the influence of distant metastasis could not be confirmed in the current literature. However, the aforementioned studies did not provide specific details on a rather reduced general condition and high risk of surgery. The exact role of distant metastasis in this context cannot be completely determined, although it is precisely this specific aspect that seems to be of extraordinary interest in the current work; in general, the presented data otherwise concur with those of the current literature that, under adequate risk assessment and exhaustive surgical preparation (prehabilitation), intestinal anastomosis should generally be the aim to effectively pursue long-term survival and ensure the best possible prognosis. An exception is made for elderly patients or those with distant metastases who, due to an increased intraoperative and postoperative complication potential (secondary disease profile, concomitant medication, and limited organ reserve; catabolic metabolic state, and immunosuppressive effects in advanced tumor stage as in metastatic tumor growth), require special attention with respect to:

1. longer lasting surgical interventions for restoring intestinal continuity after resection by anastomosis;

2. in case of urgent or emergency surgery (limited surgical preparation, increased risk of bleeding); and

3. compensation requirement for blood products, high proportions of a given pre-medication (inhibition of platelet aggregation, anticoagulation, etc.).

The therapeutic recommendation for patients with distant metastases has not yet been described in the literature, and it is relevant in the surgeon’s decision-making process.

Strengths

1. Representative sample

2. Prospective clinical systematic multicenter observational study design

3. Matched-pair analysis

4. Displayed surgical quality assurance for the reflection of the abdominal-surgery everyday life in clinical practice and as a contribution to research on clinical care

Limitations

The study has several limitations. First, it is based on registry data, which are subject to bias that may distort the interpretation of our results. To finally clarify the questions discussed above, randomized controlled studies are required. Although the formation of matched pairs is intended to allow better comparability, this could become a problem. Since the “twin groups” differ only in one characteristic (anastomosis vs. none or emergency vs. elective), many patients with a very good perioperative condition and few risk factors were excluded because they rarely underwent anus-praeter creation. Thus, it stands to reason that postoperative lethality rates are high in both surgical methods, as these patients have a poorer preoperative general condition.

Summary (learning points)

1. In principle, the elective creation of an anastomosis is recommended in histologically confirmed colon CA.

2. In colon CA patients of advanced age or with distant metastases, critical consideration of treatment options is required, in particular, with regard to the creation of an ostomy.

3. The most important prognostic factor for long-term survival is early postoperative mortality.

4. Early postoperative mortality is characterized by postoperative complications, most of which can be attributed to preoperative condition and risk factors.