Correlation of Presacral Tumour Recurrence with Tumour Metastasis and Long-Term Tumour Recurrence Risk in Patients with Rectal Cancer.

Objective: To explore the risk factors that affect long-term presacral tumour recurrence in patients with rectal cancer (RC) after radical rectal cancer resection.
Methods: In our study, a total of 50 patients with presacral tumour recurrence after radical resection of RC in our hospital between May 2017 and May 2018 were enrolled in the observation group, and the other 50 patients without presacral tumour recurrence after the resection over the same span were enrolled in the control group. The two groups were compared in distant metastatic rate and long-term recurrence, and corresponding K-M curves were drawn. Additionally, the quality of life of the two groups was also compared. Patients in both groups were assigned to a long-term recurrence group or a non-long-term recurrence group based on their long-term recurrence, and a multivariate logistic regression analysis was carried out for analysis of risk factors of long-term recurrence.
Results: The two groups were not greatly different in clinical data (P > 0.05). The observation group was higher than the control group in terms of distant metastasis and long-term recurrence (P < 0.05). In addition, the MOS 36-Item Short-Form Health Survey (SF-36) scores of the observation group were all lower than those of the control group in the eight dimensions (P < 0.05). Moreover, tumour diameter (OR: 0.315, 95% CI: 0.118-0.835), differentiation (OR: 2.652, 95% CI: 1.086-6.852), and presacral recurrence (OR: 2.370, 95% CI: 1.263-4.447) were all independent risk factors for long-term recurrence of patients undergoing radical resection of RC. Conclusions: Patients undergoing radical resection of RC face greatly higher risks of presacral tumour distant metastasis and long-term tumour recurrence, and tumour diameter ≥ 5 cm, low-differentiation degree, and presacral recurrence are independent risk factors for long-term recurrence of patients undergoing radical resection of RC. In the future, when performing radical resection of rectal cancer, it is necessary to pay attention to the changes in the above indicators in patients so as to prevent tumour recurrence.

1. Introduction

Digestive system-related cancers have always been knotty in clinical practice, and gastric cancer, colorectal cancer (CRC), liver cancer, and pancreatic cancer are common ones among them [1, 2]. CRC is a malignant tumour produced by the colon or rectal mucosal epithelium under many factors [3], with an incidence ranking third among all malignant tumours and a mortality ranking fourth among them [4]. At the current stage, patients with CRC in China mainly include patients with rectal cancer (RC), about 60–70% of all CRCs [5]. RC is difficult to diagnose due to the lack of clinical symptoms, and most patients have entered the middle or late stage at diagnosis when they show clinical symptoms and have manifested metastasis of tumour cells [6, 7]. Thus, it is imperative to analyze factors affecting the recurrence of RC to find a better treatment for cancer.

For patients meeting the surgical indications, surgical treatment is the main choice, and radical resection of RC is the only radical treatment for patients with RC at present [8, 9]. However, according to the previous statistics, patients with RC still face the risk of local recurrence after surgery. Studies have shown that the probability of recurrence in patients with RC has reached about 8–20% [10]. Especially, local recurrence will involve soft tissue and bony structure in front of the sacrum backward, which is presacral tumour recurrence. The proportion of patients with presacral tumour recurrence accounts for 15.63%–41.67% of patients with local recurrence after surgery, and the recurrence rate of presacral tumour after surgery is 2.8%–4.8% [11, 12]. Patients with presacral tumour recurrence will not only suffer unbearable pain due to the influence on bone structure but also face higher treatment difficulty, which seriously compromise their quality of life [13]. Local recurrence of RC always increases the difficulty of treatment for patients, and recurrence in different parts often causes different tumour metastasis, long-term recurrence, and prognosis [14, 15].

However, at present, there is no reliable assessment method for the prognosis and recurrence of CR, and corresponding preventive measures are lacking. This has also caused more and more patients with CR prognosis and recurrence, which has caused a great burden on the clinic. Therefore, this study probed into the correlation of presacral tumour recurrence with tumour metastasis and long-term tumour recurrence risk in patients with RC, with the aim of providing a basis and direction for clinical research.

2. Materials and Methods

2.1. Clinical Data

Totally, 50 patients with presacral tumour recurrence after radical resection of RC in our hospital between May 2017 to May 2018 were enrolled in the observation group, including 31 males and 19 females, with a mean age of 57.0 ± 9.4 years. Additionally, other 50 patients without presacral tumour recurrence after the resection over the same span were enrolled in the control group, including 29 males and 21 females, with a mean age of 56.4 ± 10.2 years. This study was carried out with permission from the ethics committee of our hospital and informed consent forms signed by all participants.

2.2. Inclusion and Exclusion Criteria

2.2.1. The Inclusion Criteria

Patients confirmed with RC by pathology, patients meeting the oncology clinical practice guideline released by the National Comprehensive Cancer Network (NCCN) [16], patients who underwent radical resection of RC, patients confirmed with presacral tumour recurrence based on CT, MRI, and pathological biopsy, and those with detailed clinical data were included.

2.2.2. The Exclusion Criteria

Patients with familial adenomatous polyposis, patients with a history of gastrointestinal diseases, patients comorbid with hypertension, diabetes, severe liver or kidney diseases, infectious diseases, or other malignant tumours, and those with mental disorders or communication disorders were excluded.

2.3. Follow-Up

All patients who underwent radical resection of RC were followed up by telephone, home visit, and reexamination for 36 months; the follow-up was ended in the case of recurrence or distant metastasis.

2.4. Outcome Measures

The observation group and control group were compared with baseline data, distant metastasis, total recurrence, and long-term recurrence, and K-M curves were drawn. Additionally, the MOS 36-Item Short-Form Health Survey (SF-36) [17] scores of the two groups were evaluated to understand their quality of life. SF-36 is a concise health questionnaire developed by the Boston Health Research Institute, which includes eight dimensions: physical function, role-physical, bodily pain, general health, vitality, social function, role emotional, and mental health. The higher the score for each dimension, the better the patient's quality of life. A multivariate logistic regression analysis (MLRA) was carried out to analyze the risk factors of long-term recurrence after radical resection of RC.

2.5. Statistical Analyses

In this study, the collected data were statistically analyzed using SPSS20.0 (Chicago SPSS Company, the United States) and visualized into figures using GraphPad Prism 7 (San Diego GraphPad Software Co., Ltd., the United States). The utilization rate of enumeration data (%) was analyzed using the chi-square test and expressed by X2. Measurement data were presented as the mean ± SD. All the measurement data were in the normal distribution. The intergroup comparison was performed using the independent samples t test. In addition, MLRA was conducted for analysis of the long-term recurrence of patients with RC after radical resection, and K-M survival analysis was conducted for analysis of the distant metastasis, recurrence, and long-term recurrence of patients. Moreover, the log-rank test was used for analysis. P < 0.05 suggests a notable difference.

3. Results

3.1. Summary of Results

The observation group was higher than the control group in terms of distant metastasis and long-term recurrence (P < 0.05). Additionally, the SF-36 scores of the observation group were all lower than those of the control group in the eight dimensions (P < 0.05). Tumour diameter, differentiation, and presacral recurrence were all independent risk factors for long-term recurrence in patients undergoing radical resection of RC.

3.2. Baseline Data of Patients

We compared the baseline data of the two groups and found no notable differences between them in gender, age, body mass index (BMI), place of residence, pathological stage, operation mode, experience in neoadjuvant therapy or adjuvant therapy, tumour diameter, and differentiation (P > 0.05, Table 1). It indicated that the two groups of patients were comparable.

Table 1

Baseline data.

		Observation group	Control group	χ 2/t	P
Gender
	Male	31 (62.00)	29 (58.00)	0.167	0.683
	Female	19 (38.00)	21 (42.00)
Age		57.0 ± 9.4	56.4 ± 10.2
BMI (kg/m2)		22.84 ± 2.15	22.42 ± 1.71
Place of residence
	Town	41 (82.00)	36 (72.00)	1.412	0.235
	Countryside	9 (18.00)	14 (28.00)
Pathological stage
	I-II	32 (64.00)	38 (76.00)	1.714	0.190
	III	18 (36.00)	12 (24.00)
Surgical approach
	Prelow contact	33 (66.00)	36 (72.00)	0.421	0.517
	Abdomen and perineum removed together	17 (34.00)	14 (28.00)
Experience in neoadjuvant therapy or adjuvant therapy
	Yes	39 (78.00)	34 (68.00)	1.268	0.260
	No	11 (22.00)	16 (32.00)
Tumour diameter
	<5 cm	30 (60.00)	39 (78.00)	3.787	0.052
	≥5 cm	20 (40.00)	11 (22.00)
Differentiation
	Highly differentiation	18 (36.00)	12 (24.00)	5.857	0.054
	Moderate differentiation	16 (32.00)	28 (56.00)
	Low-differentiation	16 (32.00)	10 (20.00)
Recurrence site
	Presacral soft tissue	27 (54.00)
	Lower sacrum	21 (42.00)
	High sacrum	2 (4.00)

3.3. Correlation of Presacral Recurrence with Distant Metastasis and Tumour Recurrence

During the prognostic follow-up, we successfully tracked all study subjects. According to comparison results of the two groups in distant metastatic rate and long-term recurrence rate, the two items in the observation group were notably higher than those in the control group (P < 0.05, Table 2).

Table 2

Correlation of presacral recurrence with distant metastasis and tumour recurrence.

	Observation group	Control group	χ 2	P
Distant metastatic	18 (36.00)	5 (10.00)	9.543	0.002
Long-term recurrence	9 (18.00)	2 (4.00)	5.005	0.025

3.4. Comparison of Patients' Surgical Conditions

Comparing the postoperative conditions of the two groups of patients, the operation time of the observation group was not different from that of the control group (P > 0.05, Figure 1(a)). However, the intraoperative blood loss of the observation group was (149.12 ± 35.23 mL), which was higher than that of the control group (128.14 ± 23.26 mL) (P > 0.05, Figure 1(b)). The hospitalization time of the observation group was (14.72 ± 3.53 d), which was higher than that of the control group (P < 0.05, Figure 2(c)).

Figure 1

Comparison of surgical conditions between the two groups. (a) Comparison of operation time. (b) Comparison of intraoperative blood loss. (c) Comparison of length of hospital stay. P < 0.05.

Figure 2

Comparison of SF-36 scores between the two groups. (a) Comparison of physiological function score. (b) Comparison of body pain score. (c) Comparison of state of health score. (d) Comparison of energy score. (e) Comparison of social function score. (f) Comparison of emotion score. (g) Comparison of mental health score. P < 0.05.

3.5. Comparison of Patients' Life Quality

The life quality of the two groups was evaluated based on their SF-36 scores, the results show that the physiological function score of the observation group was (51.37 ± 22.15), which was lower than that of the control group (P < 0.05, Figure 2(a)). The body pain score of the observation group was (64.64 ± 15.36), which was also lower than that of the control group (P < 0.05, Figure 2(b)). The state of health score of the observation group was (54.33 ± 12.85), which was lower than the state of health score of the control group (65.40 ± 9.25) (P < 0.05, Figure 2(c)). Comparing the energy scores of the two groups, the observation group was lower (P < 0.05, Figure 2(d)). The social function score of the observation group was significantly lower than that of the control group (P < 0.05, Figure 2(e)). The emotion score of the observation group was (63.45 ± 14.85), which was also lower than that of the control group (P < 0.05, Figure 2(f)). Finally, the mental health scores of the two groups were compared, the observation group was (51.27 ± 15.92), the control group was (67.94 ± 17.15), and the observation group was lower than the control group (P < 0.05, Figure 2(g)).

3.6. Univariate Analysis of Risk Factors for Long-Term Tumour Recurrence

According to the occurrence of long-term recurrence, the patients were assigned to a long-term recurrence group (n = 11) or a non-long-term recurrence group (n = 89). We carried out a univariate analysis of their clinical data and found that the two groups were greatly different in pathological stage, experience in neoadjuvant treatment or adjuvant treatment, tumour diameter, differentiation, and presacral recurrence (all P < 0.05, Table 3).

Table 3

Univariate analysis.

		Long-term recurrence group	Non-long-term recurrence group	χ 2/t	P
Gender				0.153	0.696
	Male	6 (54.55)	54 (60.67)
	Female	5 (45.45)	35 (39.33)
Age		57.6 ± 8.2	56.1 ± 9.2	0.516	0.607
BMI (kg/m2)		22.35 ± 2.15	22.00 ± 1.71	0.622	0.535
Place of residence				0.113	0.736
	Town	8 (72.73)	68 (77.27)
	Countryside	3 (27.27)	20 (22.73)
Pathological stage				6.956	0.008
	I-II	4 (36.36)	68 (74.73)
	III	7 (63.64)	23 (25.27)
Surgical approach				1.207	0.272
	Prelow contact	6 (54.55)	63 (70.79)
	Abdomen and perineum removed together	5 (45.45)	26 (29.21)
Experience in neoadjuvant therapy or adjuvant therapy				8.417	0.004
	Yes	4 (36.36)	69 (77.53)
	No	7 (63.64)	20 (22.47)
Tumour diameter				14.920	0.001
	<5 cm	2 (18.18)	67 (75.28)
	≥5 cm	9 (81.82)	22 (24.72)
Differentiation				9.321	0.010
	Highly differentiation	1 (11.11)	29 (32.58)
	Moderate differentiation	3 (22.22)	41 (46.07)
	Low differentiation	7 (66.67)	19 (21.35)
Presacral recurrence				5.005	0.025
	Yes	9 (81.82)	41 (46.07)
	No	2 (18.18)	48 (53.93)

3.7. Multivariate Analysis

We included the indicators with differences in univariate analysis into the assignment (Table 4), and then chose to go forward: MLRA based on LR showed that pathological stage and experience in neoadjuvant therapy or adjuvant therapy were not independent risk factors for patients' long-term recurrence, but tumour diameter (OR: 0.315, 95% CI: 0.118–0.835), differentiation (OR: 2.652, 95% CI: 1.086–6.852), and presacral recurrence (OR: 2.370, 95% CI: 1.263–4.447) were all independent risk factors for long-term recurrence of patients undergoing radical resection of RC (Table 5).

Table 4

Assignment.

Factors	Assignment
Pathological stage	III = 1, I-II = 0
Experience in neoadjuvant therapy or adjuvant therapy	No = 0, yes = 1
Tumour diameter	<5 cm = 0, ≥5 cm = 1
Differentiation	Highly differentiation = 1, moderate differentiation = 2, and low differentiation = 3
Presacral recurrence	Yes = 1, no = 0
Long-term recurrence	Long-term recurrence = 1, survival = 0

Table 5

Multivariate analysis.

Factors	B	S.E.	Wals	P	Exp (B)	95% CI of Exp (B).
						Lower limit	Upper limit
Pathological stage	0.903	0.482	3.762	0.056	2.934	1.186	6.851
Experience in neoadjuvant therapy or adjuvant therapy	1.171	0.483	10.876	0.065	3.310	1.120	6.799
Tumour diameter	1.156	0.498	5.387	0.020	0.315	0.118	0.835
Differentiation	1.022	0.475	4.824	0.036	2.652	1.086	6.852
Presacral recurrence	0.865	0.338	7.228	0.007	2.370	1.263	4.447

4. Discussion

Laparoscopic radical resection is a common operation for early CRC, which can help complete cancer tissue resection and digestive tract reconstruction by puncture directly to the focus of the cancer with the help of laparoscopic vision. It features with simple operation and advantages in bringing less trauma, less complications, and quick recovery, and its efficacy receives gradual recognition [18-20]. However, according to relevant studies in recent years, patients with CRC still suffer recurrence and metastasis after surgery because of the complicated colorectal lymphatic drainage, abundant blood supply, interconnection and densely distribution of CRC cells, difficulty in inhibiting the cells, and their inclination to metastasis. Therefore, we should pay attention to the postoperative situation of patients with RC and prevent the deterioration of the disease in time, thus improving the life quality and long-term prognosis of patients [21, 22]. Presacral tumour recurrence is a subtype of locally recurrent RC. Because of the involvement of the presacral fascia or bone, the tumour is fixed behind the pelvis, which greatly increases the treatment difficulty. There are many difficulties in the diagnosis and therapy of presacral recurrence, and there is not much consensus on a unified diagnosis and therapy. At present, its diagnosis is based on clinical symptoms, imaging, endoscopy, tumour marker detection, pathological biopsy, and surgery, chemotherapy, or radiotherapy is selected as the specific treatment method according to the patient's condition [23-25]. The feasibility and specific measures of operation depend on the anatomical characteristics of recurrent tumours, but there is still a lot of controversy about the adoption of surgical methods. One study by Guo et al. [26] mentioned the effect of different surgical methods on the efficacy of RC patients with presacral tumour recurrence. Specifically, the incidence of dysfunction after sacrectomy was 50%, significantly higher than the other two groups, but there was no difference in postoperative survival rate, and the 1-year survival rate of patients was about 85% regardless of the surgical method. Local recurrence is common after radical resection of RC, and surgery is one of the optimal treatment options. However, extensive pelvic organ resection is usually needed to obtain a negative margin, which leads to a high incidence of postoperative complications, and serious complications will compromise the prognosis of patients. One study by Paku et al. [27] has revealed that low preoperative nutritional prognosis index and excessive intraoperative blood loss are risk factors for severe postoperative complications of locally recurrent RC, which can improve the prevention of severe postoperative complications of locally recurrent RC to a certain extent.

In our present study, after radical resection of RC, patients with presacral tumour recurrence showed a notably higher tumour metastasis rate and a notably higher long-term tumour recurrence rate than those without presacral tumour recurrence. According to the K-M curves, patients with presacral tumour recurrence had worse distant metastasis, total recurrence, and long-term recurrence than those without it. We also studied the influence of presacral tumour recurrence on patients' quality of life. The life quality of patients undergoing radical resection of RC has always needed to be improved because the resection may cause pelvic autonomic nerve injury, urinary, and sexual dysfunction, which are the most common complications after RC surgery. At present, there are some solutions. For instance, one study by Wei and Fang [28] has pointed out that total mesorectal resection with preservation of anterior rectal fascia can effectively reduce the incidence of postoperative urination and sexual dysfunction in male patients with middle or low RC, and most importantly, it will not compromise the curative effect on and prognosis of patients. In one study by Cao et al. [29], radiotherapy, and chemotherapy in the perioperative period have strongly reduced local recurrence and improved long-term survival rates, but despite the fact that they can improve patients' prognosis, they would greatly increase the incidence of adverse reactions such as defecation, urination, and sexual dysfunction, and further lower the quality of life of patients. According to the results of our study, patients with presacral tumour recurrence got notably lower SF-36 scores in the 8 dimensions than those without it. Patients with presacral recurrence are often accompanied by unbearable pain. If the recurrence is not controlled immediately by surgery, the patients often need multiple courses of chemotherapy or radiotherapy for disease control. During these courses, analgesics are also needed for pain alleviation [30], which will undoubtedly lower the scores of patients' physical pain, health status, energy, and mental health. Therefore, psychological treatment is also required to improve their psychological status. At the end of the study, we analyzed the risk factors for long-term recurrence of patients undergoing radical resection of RC via MLRA. Long-term recurrence refers to a recurrence 5 years after the operation. Short-term local recurrence is common after radical resection of RC, but long-term recurrence also needs attention. The study of long-term recurrence needs a long-run follow-up, so corresponding studies are rare. Wang et al. [31] have studied the 3-year recurrence-free survival rate (RFSR) patients undergoing radical resection of RC by the K-M method. In their study, no obvious difference was found between patients with RC who showed a complete clinical response to neoadjuvant chemotherapy and those who received radical resection of RC in 3-year RFSR. Therefore, neoadjuvant chemotherapy might be a promising conservative choice for aggressive radical surgery, but they have not conducted a longer-term follow-up study, so the tumour metastasis and recurrence after more than 5 years are unclear. According to our MLRA, tumour diameter ≥ 5 cm, low-differentiation degree, and presacral recurrence were all independent risk factors for long-term recurrence of patients undergoing radical resection of RC. The results suggest that tumour diameter, differentiation degree, and presacral recurrence can be used as predictive indicators of long-term recurrence of patients.

At present, there is no reliable assessment method for the prognosis and recurrence of CR in clinical practice, so there is also a lack of corresponding preventive measures. Through the results of this study, we can form a preliminary concept for preventing the recurrence of CR prognosis, which is of great significance for ensuring the safety of patients' lives. However, this study still has some limitations. First, the samples included in this study are patients undergoing radical resection of RC, and those treated by other methods, such as radiotherapy and chemotherapy, are not included. Second, we have not deeply studied the influence of various treatment methods on patients with presacral recurrence. Finally, we have not carried out in vitro cell studies or animal experiments. Therefore, we hope to explore the mechanism of presacral recurrence more in future studies.

To sum up, patients undergoing radical resection of RC face greatly higher risks of presacral tumour distant metastasis and long-term tumour recurrence, and tumour diameter ≥ 5 cm, low-differentiation degree and presacral recurrence are independent risk factors for long-term recurrence of patients undergoing radical resection of RC.