
==== Front
Int J Surg
Int J Surg
JS9
International Journal of Surgery (London, England)
1743-9191
1743-9159
Lippincott Williams & Wilkins Hagerstown, MD

38768462
IJS-D-23-02669
10.1097/JS9.0000000000001646
00003
3
Original Research
Prognostic stratification of patients with pT4bN0M0 colorectal cancer following multivisceral resection: a multi-institutional case series analysis
Quan Jichuan MD aqjchsh@163.com

Zuo Kai MD ezuokai1800@163.com

Li Guoli MD d64342474@qq.com

Liu Junguang MD cliujunguang1984@126.com

Mei Shiwen MD amswbxw@163.com

Hu Gang MD adoctorhuhu@126.com

Qiu Wenlong MD aWenlongQiu2015@163.com

Zhuang Meng MD azhuangmeng2015@126.com

Meng Ling MD edrmeng@163.com

Wang Xishan MD a*wxshan1208@126.com

Chang Hu MD changhu2@163.com
b*
Tang Jianqiang MD a*doc_tjq@hotmail.com

a Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
b Department of Hospital Administration Office, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
c Department of General Surgery, Peking University First Hospital, Beijing
d Department of Anorectal Surgery, Chifeng Municipal Hospital, Chifeng
e Department of Gastrointestinal Surgery, Linfen People’s Hospital, Linfen, Shanxi, People’s Republic of China
* Corresponding author. Address: Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing 100021, People’s Republic of China. E-mail: doc_tjq@hotmail.com (J. Tang), and E-mail: wxshan1208@126.com (X. Wang); Department of Hospital Administration Office, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuan Nanli, Chaoyang District, Beijing 100021, People’s Republic of China. Tel.: +86 010 877 871 10. E-mail: changhu2@163.com (H. Chang).
9 2024
20 5 2024
110 9 53235333
23 11 2023
6 5 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/

Background:

Colorectal cancer (CRC) patients with stage pT4b are a complex group as they show differences in tumor-infiltrated organs. Patients with the same stage often exhibit differences in prognosis after multivisceral resection (MVR). Thus far, some important prognostic factors have not been thoroughly investigated. Here, we identified the prognostic factors influencing CRC patients at the pT4bN0M0 stage to stratify the prognostic differences among patients.

Materials and methods:

A retrospective analysis was conducted on patients diagnosed with locally advanced CRC and who underwent MVR at three medical institutions from January 2010 to December 2021. The prognostic factors affecting the survival of CRC patients at pT4bN0M0 stage were identified by multivariate Cox proportional hazard models. We then classified the prognosis into different grades on the basis of these independent prognostic factors.

Results:

We enrolled 690 patients with locally advanced CRC who underwent MVR; of these, 172 patients with pT4bN0M0 were finally included. Patients with digestive system [overall survival (OS): hazard ratio (HR)=0.441; 95% confidence interval (CI)=0.217–0.900; P=0.024; disease-free survival (DFS): HR=0.416; 95% CI=0.218–0.796; P=0.008) or genitourinary system invasion (OS: HR=0.405; 95% CI=0.193–0.851; P=0.017; DFS: HR=0.505; 95% CI=0.267–0.954; P=0.035) exhibited significantly better OS and DFS as compared to those with gynecological system invasion, while the OS and DFS were similar between the digestive system and genitourinary system invasion groups (OS: HR=0.941; 95% CI=0.434–2.042; P=0.878; DFS: HR=1.211; 95% CI=0.611–2.403; P=0.583). Multivariate analysis showed that age (OS: HR=2.121; 95% CI=1.157–3.886; P=0.015; DFS: HR=1.869; 95% CI=1.116–3.131; P=0.017) and type of organs invaded by CRC (OS: HR=3.107; 95% CI=1.121–8.609; P=0.029; DFS: HR=2.827; 95% CI=1.142–6.997; P=0.025) were the independent prognostic factors that influenced the OS and DFS of CRC patients with pT4bN0M0 disease. The OS and DFS of patients showing invasion of the gynecological system group were significantly worse (P=0.004 and P=0.003, respectively) than those of patients with invasion of the nongynecological system group. On the basis of the above-mentioned two independent prognostic factors, patients were assigned to high-risk, medium-risk, and low-risk groups. Subgroup analysis showed that the OS and DFS of the medium-risk and high-risk groups were significantly worse (P=0.001 and P=0.001, respectively) than those of the low-risk group.

Conclusion:

Patients with pT4bN0M0 CRC show significant differences in their prognosis. The type of organs invaded by CRC is a valuable indicator for prognostic stratification of CRC patients with pT4bN0M0.

Keywords:

case series
colorectal cancer
multivisceral resection
organ type
prognostic stratification
OPEN-ACCESSTRUE
==== Body
pmcIntroduction

Highlights

Colorectal cancer (CRC) patients exhibiting the same disease stage show differences in prognosis, and the overall survival (OS) and disease-free survival (DFS) differ significantly among CRC patients with pT4bN0M0 disease.

The type of organs invaded by CRC is a new prognostic indicator. The prognosis was significantly worse for patients with CRC invasion of gynecological system organs than for those with CRC invasion of nongynecological system organs.

The sub-classification of organs affected by CRC invasion is an effective approach to identify prognostic differences among patients with pT4bN0M0 CRC; this prognostic indicator is helpful in optimizing the classification of T4 stage CRC.

The type of organs invaded by CRC and age were the independent prognostic factors in patients with pT4bN0M0 CRC. These factors, when combined, more accurately stratified the prognosis of these patients and improved the ability to predict their survival.

Locally advanced CRC has a high incidence of recurrence, metastasis, and poor prognosis. It is, therefore, crucial to improve treatment and management approaches for patients with locally advanced CRC. At the initial diagnosis, the adjacent organs or structures show invasion in approximately 5%–15% of CRC patients1. Multivisceral resection (MVR) is the only approach with high significance to achieve radical treatment of patients with locally advanced CRC and improve their long-term survival. However, because these tumors are larger and have a wider scope of invasion, it becomes more difficult to perform their surgical resection; moreover, MVR for locally advanced CRC cannot be performed in all hospitals. Among the overall CRC, CRC with pT4b is a relatively rare entity; furthermore, the inadequate number of cases of CRC with pT4b and the difficulty in operating limit comprehensive and in-depth research on these patients.

The tumor node metastasis (TNM) staging system developed by the American Joint Committee on Cancer (AJCC) is commonly utilized for predicting cancer prognosis and guiding treatment. Based on this system, patients with the same cancer stage should exhibit a similar survival outcome. However, in clinical practice, some patients with stage pT4bN0M0 CRC often show differences in their survival, thus indicating the limitations of the current TNM staging system. CRC patients with stage pT4b disease are a complex and unique group, and the diversity and complexity of the invaded organs pose a remarkable challenge to treatment. Because of the complexity of stage pT4b CRC, several crucial factors have not been adequately researched; consequently, the current TNM staging system cannot comprehensively and precisely evaluate the prognosis of this patient group. Hence, we believe that the current clinical practice should focus more on the uniqueness and particularity of stage pT4b CRC. Presently, most studies on MVR of CRC are limited to single-center studies and small sample data2–9. Some previous studies have analyzed patients with the clinical T4b (cT4b) stage. However, in some cT4b patients, the tumor does not invade the adjacent organs because of inflammatory adhesions. Thus, evaluating how the number and type of organs removed affect patient prognosis is not sufficiently accurate from the perspective of cT4b rather than pT4b. Consequently, more accurately predicting the prognosis of CRC patients with stage pT4b disease and developing robust personalized management approaches are the concerns that need to be addressed.

Therefore, the present study examined the prognostic factors of CRC patients with stage pT4bN0M0 disease based on true tumor invasion and then stratified the prognosis of these patients to determine survival differences among different patients; this approach will help enhance the precision of the current TNM staging system for CRC.

Materials and methods

Study population

The clinicopathological data of CRC patients who underwent MVR at three medical centers in China from January 2010 to December 2021 were retrospectively analyzed. The three centers were high-volume hospitals with extensive experience in CRC surgery, and experienced surgeons performed the MVR. The study was registered in ClinicalTrials and received approval from the relevant institutional ethics committees. The registration unique identifying number is NCT06115837. Hyperlink to the specific registration: https://clinicaltrials.gov/study/NCT06115837. This case series has been reported in line with the PROCESS 2023 (www.processguideline.com) criteria10.

Patients meeting the following inclusion and exclusion criteria were selected for data analysis. Inclusion criteria: CRC patients with primary adenocarcinoma as pathologically confirmed lesions; patients showing direct invasion of other structures or organs by the pathologically confirmed tumor; patients with pT4bN0M0 stage CRC; and patients with R0 resection. Exclusion criteria: patients exhibiting distant metastasis; patients with pN1 or pN2 staging; patients with R1 or R2 resection; patients with a pathologically confirmed tumor with inflammatory adhesions to other organs or structures; and patients with recurrent CRC or other concurrent malignant tumors.

Data collection

The clinicopathological data analyzed included age, gender, smoking history, BMI, serum albumin, hemoglobin, pulmonary function, operation date, and concomitant diseases (including hypertension, cardiopathy, diabetes, or cerebrovascular disease; these concomitant diseases were evaluated and treated before surgery), history of abdominal surgery, complications at diagnosis (including ileus, perforation, bleeding, rectovesical fistula, or rectovaginal fistula), preoperative chemotherapy/radiotherapy, carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) levels, operation type, tumor location, and size, tumor differentiation, perineural invasion, lymphovascular invasion, type of organs invaded by CRC, number of organs invaded by CRC, number of organ systems invaded by CRC, postoperative adjuvant therapy, postoperative complications, TNM stage, and survival time. Tumor differentiation was divided into well-differentiated, moderately differentiated, and poorly differentiated. According to the 2010 World Health Organization criteria11, well-differentiated, moderately differentiated, and poorly differentiated tumors were defined as tumors composed of >95% isolated tubular glands, those composed of 50%–95% glandular structures, and those composed of <50% glands, respectively. DFS is defined as the time from the surgery to tumor recurrence or distant metastasis. OS was calculated as the time interval between surgery and death. Pathological staging was evaluated using the AJCC (8th ed.) staging system.

In accordance with the TNM staging system of the AJCC, the direct invasion or adhesion of the tumor to adjacent organs or structures is considered stage T4b. In this study, only those patients whose tumors had invaded the adjacent organs or structures were included, whereas patients in whom tumors showed adherence to the adjacent organs or structures were excluded. MVR involved the resection of the CRC lesion and the infiltrated adjacent organs or structures, which included the small intestine, liver, bladder, ureter, uterus, ovary, etc. Because of the diverse range of infiltrated organs, we divided MVR into four categories based on the type of infiltrated adjacent organs: the digestive system, including additional bowel resection, gastrectomy, pancreas, liver, and gallbladder; the genitourinary system, including additional resection of the bladder, ureter, seminal vesicle, prostate, kidney, adrenal gland, or vas deferens; the gynecological system, including additional resection of the uterus, vagina, or ovary; other organs or structures, such as the spleen, and abdominal wall.

Follow-up

Patient follow-up was achieved through outpatient examination or telephonic calls. The follow-up frequency was as follows: 3-month interval for the first 2 years after surgery, 6-month interval for 3–5 years after surgery, and annually thereafter. Follow-up approaches utilized were physical examination, assessment of serum levels of tumor markers, colonoscopy, and computed tomography scan of the abdomen, chest, and pelvic region. The loss to follow-up rate was 8.1% for DFS and 11.6% for OS.

Statistical analysis

Normally distributed continuous variables were expressed in the form of mean±SD, nonnormally distributed continuous variables were presented as median with interquartile range, and categorical variables were expressed as numbers with percentages. The one-way analysis of variance or Kruskal–Wallis test was used to compare continuous variables; Fisher’s exact test or the χ 2 test was used to compare categorical variables. The Kaplan–Meier survival method was utilized to construct survival curves. Furthermore, differences in survival outcomes among the groups were compared with log-rank tests. Univariate and multivariate analyses of OS and DFS were conducted with Cox proportional hazards models. Variables with a P value of less than 0.20 in univariate analysis were subjected to a multivariate Cox analysis. We performed a prognostic stratification analysis by utilizing the independent prognostic factors identified from the multivariate analysis. Patients were classified into low-risk, medium-risk, and high-risk groups based on the difference in prognosis between the subgroups for each independent prognostic factor. We combined variables with a good prognosis subgroup from each independent prognostic factor and assigned them to low-risk groups; variables with a poor prognosis subgroup from each independent prognostic factor were combined and assigned to high-risk groups, and other variables were assigned to the medium-risk group. The OS and DFS of patients with low-risk, medium-risk, or high-risk groups were compared by Cox analysis, and the corresponding hazard ratio (HR) and 95% confidence interval (CI) were estimated. P value <0.05 was considered statistically significant. SPSS, version 26.0 (IBM Corp., Armonk, NY), and R v4.3.3 were used to perform all statistical analyses.

Results

Basic characteristics of the patients

From January 2010 to December 2021, MVR was performed on 690 patients with T4b CRC. On the basis of the inclusion and exclusion criteria, 518 patients were excluded. Finally, 172 patients (98 males and 74 females; mean age: 60.74 years) with pT4bN0M0 CRC were included. The flow chart is provided in Figure 1.

Figure 1 Flow chart.

Of these 172 patients, open and laparoscopic surgeries were performed on 58.1% and 41.9% of the patients, respectively. The middle/lower rectum was the localization site of the primary tumor in 54 patients, the upper rectum/rectosigmoid junction was the localization site of the primary tumor in 50 patients, and the colon was the localization site of the primary tumor in 68 patients. Histologically, 62.8% of the patients showed well or moderately differentiated tumors, and 37.2% of the patients showed poorly differentiated tumors. Types and numbers of tumor-infiltrated organs were as follows: one extra organ was invaded in 133 cases, and two or more extra organs were invaded in 39 patients. Based on the categories of the infiltrated organs, the gynecological system group (no matter how many organ systems were involved, as long as gynecological organs were involved, they were classified as this group) and the nongynecological system group (digestive system, genitourinary system, and other organs or structures) included 51 and 121 patients, respectively.

The clinicopathological data of patients from three centers were also evaluated. Significant statistical differences were observed among the three centers in terms of concomitant diseases (P=0.042), history of abdominal surgery (P=0.028), and operative type (P=0.028). The percentage of concomitant diseases was higher in center 2, while the percentage of the history of abdominal surgery and open operation was lower in center 3. In addition to concomitant diseases, history of abdominal surgery, and operative type, the distribution of other patient characteristics was largely consistent among the centers. The detailed baseline characteristics are provided in Table 1.

Table 1 Clinicopathological features of patients with pT4bN0M0 colorectal cancer, n (%).

Variables	Overall (n=172)	Center 1 (n=68)	Center 2 (n=78)	Center 3 (n=26)	P	
Age, mean±SD, years	60.74±12.49	60.66±12.37	61.14±13.67	59.77±8.91	0.888	
Gender					0.424	
 Male	98 (57.0)	35 (51.5)	46 (59.0)	17 (65.4)		
 Female	74 (43.0)	33 (48.5)	32 (41.0)	9 (34.6)		
BMI, median (IQR), kg/m2	22.68 (20.70–24.73)	22.86 (20.77–24.70)	22.50 (20.70–25.03)	21.85 (20.58–24.43)	0.779	
Hb, g/l	113.69±23.33	115.78±25.37	112.09±22.84	113.04±19.27	0.631	
Alb, g/l	37.42±5.88	38.47±6.48	36.53±5.23	37.35±5.85	0.136	
Smoking history					0.758	
 No	127 (73.8)	52 (76.5)	57 (73.1)	18 (69.2)		
 Yes	45 (26.2)	16 (23.5)	21 (26.9)	8 (30.8)		
Pulmonary function					0.752	
 Normal	87 (50.6)	36 (52.9)	37 (47.4)	14 (53.8)		
 Abnormal	85 (49.4)	32 (47.1)	41 (52.6)	12 (46.2)		
Operation date (years)					0.263	
 2010–2015	78 (45.3)	32 (47.1)	38 (48.7)	8 (30.8)		
 2016–2021	94 (54.7)	36 (52.9)	40 (51.3)	18 (69.2)		
Concomitant diseases					0.042	
 No	86 (50.0)	41 (60.3)	31 (39.7)	14 (53.8)		
 Yes	86 (50.0)	27 (39.7)	47 (60.3)	12 (46.2)		
History of abdominal surgery					0.028	
 No	139 (80.8)	48 (70.6)	68 (87.2)	23 (88.5)		
 Yes	33 (19.2)	20 (29.4)	10 (12.8)	3 (11.5)		
Preoperative chemotherapy/radiotherapy					0.442	
 No	123 (71.5)	45 (66.2)	59 (75.6)	19 (73.1)		
 Yes	49 (28.5)	23 (33.8)	19 (24.4)	7 (26.9)		
CEA, ng/ml	4.93 (2.61–19.98)	4.54 (2.52–17.70)	5.59 (2.86–20.92)	5.91 (2.55–19.90)	0.796	
CA19–9, U/ml	15.18 (7.69–29.70)	14.32 (7.44–30.96)	15.86 (8.49–25.79)	18.44 (6.38–58.90)	0.920	
Complications at diagnosis					0.373	
 No	139 (80.8)	58 (85.3)	62 (79.5)	19 (73.1)		
 Yes	33 (19.2)	10 (14.7)	16 (20.5)	7 (26.9)		
Operative type					0.028	
 Open	100 (58.1)	41 (60.3)	50 (64.1)	9 (34.6)		
 Laparoscopic	72 (41.9)	27 (39.7)	28 (35.9)	17 (65.4)		
Tumor location					0.272	
 Middle/lower rectum	54 (31.4)	25 (36.8)	18 (23.1)	11 (42.3)		
 Upper rectum/rectosigmoid junction	50 (29.1)	19 (27.9)	24 (30.8)	7 (26.9)		
 Colon	68 (39.5)	24 (35.3)	36 (46.2)	8 (30.8)		
Tumor size, cm	6.00 (4.85–8.50)	6.00 (4.00–8.00)	6.50 (5.50–9.00)	6.25 (4.88–9.13)	0.082	
Tumor differentiation					0.441	
 Well-moderate	108 (62.8)	40 (58.8)	49 (62.8)	19 (73.1)		
 Poor	64 (37.2)	28 (41.2)	29 (37.2)	7 (26.9)		
Number of organs invaded by CRC					0.534	
 One	133 (77.3)	53 (77.9)	58 (74.4)	22 (84.6)		
 Two or more	39 (22.7)	15 (22.1)	20 (25.6)	4 (15.4)		
Number of organ systems invaded by CRC					0.349	
 One system	155 (90.1)	59 (86.8)	71 (91.0)	25 (96.2)		
  Only gynecological system	43 (25.0)	20 (29.4)	16 (20.5)	7 (26.9)		
  Only digestive system	54 (31.4)	19 (27.9)	29 (37.2)	6 (23.1)		
  Only genitourinary system	53 (30.8)	19 (27.9)	23 (29.5)	11 (42.3)		
  Only orther organs or structures	5 (2.9)	1 (1.5)	3 (3.8)	1 (3.8)		
 Two or more systems	17 (9.9)	9 (13.2)	7 (9.0)	1 (3.8)		
Type of organs invaded by CRC					0.248	
 Gynecological system	51 (29.7)	25 (36.8)	19 (24.4)	7 (26.9)		
 Nongynecological system	121 (70.3)	43 (63.2)	59 (75.6)	19 (73.1)		
Number of organs invaded within the gynecological system group					0.287	
 One	39 (76.5)	19 (76.0)	13 (68.4)	7 (100.0)		
 Two or more	12 (23.5)	6 (24.0)	6 (31.6)	0 (0.0)		
Number of organs invaded within the nongynecological system group					0.956	
 One	94 (77.7)	34 (79.1)	45 (76.3)	15 (78.9)		
 Two or more	27 (22.3)	9 (20.9)	14 (23.7)	4 (21.1)		
Postoperative adjuvant therapy					0.200	
 No	46 (26.7)	14 (20.6)	26 (33.3)	6 (23.1)		
 Yes	126 (73.3)	54 (79.4)	52 (66.7)	20 (76.9)		
Lymphovascular invasion					0.310	
 Negative	149 (86.6)	56 (82.4)	71 (91.0)	22 (84.6)		
 Positive	23 (13.4)	12 (17.6)	7 (9.0)	4 (15.4)		
Perineural invasion					0.695	
 Negative	140 (81.4)	53 (77.9)	65 (83.3)	22 (84.6)		
 Positive	32 (18.6)	15 (22.1)	13 (16.7)	4 (15.4)		
Postoperative complications					0.343	
 No	138 (80.2)	58 (85.3)	61 (78.2)	19 (73.1)		
 Yes	34 (19.8)	10 (14.7)	17 (21.8)	7 (26.9)		
Alb, albumin; CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CRC, colorectal cancer; Hb, hemoglobin; IQR, interquartile range.

Long‑term oncological outcomes and results of the survival analysis

The 3-year and 5-year OS were 76.2% and 61.1%, respectively, and the 3-year and 5-year DFS were 69.9% and 57.3%, respectively. For OS, we first compared the survival differences among the gynecological system, digestive system, and genitourinary system (other organs or structures were not compared because of the small number of cases). Survival analysis showed that the OS of patients with only digestive system (HR=0.441; 95% CI=0.217–0.900; P=0.024) or genitourinary system invasion (HR=0.405; 95% CI=0.193–0.851; P=0.017) was significantly better than that of patients with only gynecological system invasion, while there was no statistically significant difference in survival between the digestive system and genitourinary system groups (HR=0.941; 95% CI=0.434–2.042; P=0.878) (Table 2). Based on the results of the survival analysis, we divided the type of organs invaded by CRC into the gynecological system group and a nongynecological system group (digestive system, genitourinary system, and other organs or structures). The univariate prognostic analysis revealed that age and the type of organs invaded by CRC were the critical factors that affected patient prognosis; however, the groups did not exhibit significant differences in gender, smoking history, BMI, serum albumin, hemoglobin, pulmonary function, operation date, concomitant diseases, complications at diagnosis, CEA and CA19-9 levels, preoperative chemotherapy/radiotherapy, operation type, tumor location, lymphovascular invasion, perineural invasion, tumor differentiation, tumor size, number of organs invaded by CRC, number of organ systems invaded by CRC, number of organs invaded within the nongynecological system group, number of organs invaded within the gynecological system group, type of gynecological system organs invaded by CRC, different medical centers, postoperative adjuvant therapy, or postoperative complications. A multivariate analysis was then conducted using the variables with P value < 0.20 in the univariate analysis. As illustrated in Table 3, age (HR=2.121; 95% CI=1.157–3.886; P=0.015) and the type of organ invaded by CRC (HR=3.107; 95% CI=1.121–8.609; P=0.029) were the independent factors affecting OS. Patients aged ≥60 years exhibited significantly worse 5-year OS as compared to those aged <60 years (51.0% vs. 73.4%, P=0.013) (Fig. 2). Moreover, CRC patients showing invasion of the gynecological organs had significantly worse 5-year OS than CRC patients showing invasion of the nongynecological organs (41.8% vs. 66.7%, P=0.004) (Fig. 3).

Table 2 Overall survival analysis for the different organ systems invaded by colorectal cancer.

Variables	HR (95% CI)	P	HR (95% CI)	P	
Only the gynecological system invasion group	—	—			
Only the digestive system invasion group	0.441 (0.217–0.900)	0.024	—	—	
Only the genitourinary system invasion group	0.405 (0.193–0.851)	0.017	0.941 (0.434–2.042)	0.878	
CI, confidence interval; HR, hazard ratio.

Table 3 Univariate and multivariate analyses of overall survival of patients with pT4bN0M0 colorectal cancer.

	Overall survival	
	Univariable analysis	Multivariate analysis	
Variables	HR (95% CI)	P	HR (95% CI)	P	
Age (≥60/<60 years)	2.084 (1.150–3.777)	0.015	2.121 (1.157–3.886)	0.015	
Gender (female/male)	1.475 (0.851–2.556)	0.166	0.544 (0.206–1.435)	0.219	
BMI (≥24/<24 kg/m2)	1.367 (0.761–2.455)	0.296			
Hb (≥120/<120 g/l)	0.988 (0.563–1.735)	0.967			
Alb (≥40/<40 g/l)	1.120 (0.625–2.007)	0.704			
Smoking history (yes/no)	0.991 (0.518–1.896)	0.978			
Pulmonary function (abnormal/normal)	1.062 (0.612–1.843)	0.831			
Operation date (2016–2021/2010–2015)	0.733 (0.413–1.302)	0.290			
Concomotant diseases (yes/no)	1.258 (0.722–2.190)	0.418			
Complications at diagnosis (yes/no)	1.306 (0.695–2.454)	0.407			
CEA level (>5/≤5 ng/ml)	1.345 (0.772–2.341)	0.295			
CA19-9 level (>37/≤37 U/ml)	0.987 (0.494–1.972)	0.971			
Preoperative chemotherapy/radiotherapy (yes/no)	0.772 (0.403–1.479)	0.436			
Operative type（laparoscopic/open）	0.729 (0.401–1.323)	0.299			
Tumor location	
 Middle/lower rectum	—	—			
 Upper rectum/rectosigmoid junction	0.977 (0.477–2.001)	0.949			
 Colon	0.859 (0.441–1.673)	0.655			
Lymphovascular invasion (yes/no)	1.444 (0.569–3.660)	0.439			
Perineural invasion (yes/no)	1.426 (0.713–2.852)	0.315			
Tumor differentiation (poor/well-moderate)	1.306 (0.747–2.284)	0.349			
Tumor size (≥6/<6 cm)	0.614 (0.352–1.071)	0.086	0.788 (0.425–1.459)	0.448	
Type of organs invaded by CRC (gynecological system/nongynecological system)	2.261 (1.282–3.987)	0.005	3.107 (1.121–8.609)	0.029	
Number of organs invaded by CRC (two or more/one)	1.043 (0.546–1.992)	0.899			
Number of organ systems invaded by CRC (two or more/one)	1.617 (0.728–3.592)	0.238			
Number of organs invaded within the nongynecological system group (two or more/one)	0.780 (0.320–1.902)	0.585			
Number of organs invaded within the gynecological system group (two or more/one)	1.439 (0.540–3.833)	0.467			
Type of gynecological system organs invaded by CRC	
 Uterus	—	—			
 Ovary	0.940 (0.203–4.355)	0.937			
 Vagina	0.915 (0.257–3.252)	0.891			
 Two or more	1.176 (0.330–4.196)	0.802			
Medical centers	
 Center 1	—	—			
 Center 2	0.857 (0.458–1.603)	0.629			
 Center 3	1.074 (0.474–2.436)	0.864			
Postoperative adjuvant therapy (yes/no)	0.736 (0.407–1.331)	0.311			
Postoperative complications (yes/no)	0.947 (0.461–1.947)	0.883			
Alb, albumin; CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CI, confidence interval; CRC, colorectal cancer; Hb, hemoglobin; HR, hazard ratio.

Figure 2 Overall survival curves for pT4bN0M0 colorectal cancer patients of different ages.

Figure 3 Overall survival curves for pT4bN0M0 CRC patients with different types of organs invaded by CRC. CRC, colorectal cancer.

Regarding DFS, we compared the survival differences among the gynecological system, digestive system, and genitourinary system. Survival analysis showed that the DFS of patients with only digestive system (HR=0.416; 95% CI=0.218–0.796; P=0.008) or genitourinary system invasion (HR=0.505; 95% CI=0.267–0.954; P=0.035) was significantly better than that of patients with only gynecological system invasion, while there was no statistically significant difference in survival between the digestive system and genitourinary system groups (HR=1.211; 95% CI=0.611–2.403; P=0.583) (Table 4). The univariate prognostic analysis showed that age, number of organ systems invaded by CRC, and the type of organs invaded by CRC were the critical factors that affected patient prognosis; however, no significant differences were observed in gender, smoking history, BMI, serum albumin, hemoglobin, pulmonary function, operation date, concomitant diseases, complications at diagnosis, CEA and CA19-9 levels, preoperative chemotherapy/radiotherapy, operation type, tumor location, lymphovascular invasion, perineural invasion, tumor differentiation, tumor size, number of organs invaded by CRC, number of organs invaded within the nongynecological system group, number of organs invaded within the gynecological system group, type of gynecological system organs invaded by CRC, different medical centers, postoperative adjuvant therapy, or postoperative complications. Variables with P value <0.20 in the univariate analysis were entered into the multivariate analysis for determining the final independent prognostic factors. Table 5 shows that age (HR=1.869; 95% CI=1.116–3.131; P=0.017) and type of organs invaded by CRC (HR=2.827; 95% CI=1.142–6.997; P=0.025) were the independent factors influencing DFS. Patients aged ≥60 years displayed significantly worse 5-year DFS as compared to those aged <60 years (46.7% vs. 69.6%, P=0.015) (Fig. 4). Similarly, Figure 5 shows that patients with CRC invasion of the gynecological organs exhibited significantly worse 5-year DFS than those with CRC invasion of the nongynecological organs (40.5% vs. 63.3%, P=0.003).

Table 4 Disease-free survival analysis for the different organ systems invaded by colorectal cancer.

Variables	HR (95% CI)	P	HR (95% CI)	P	
Only the gynecological system invasion group	—	—			
Only the digestive system invasion group	0.416 (0.218–0.796)	0.008	—	—	
Only the genitourinary system invasion group	0.505 (0.267–0.954)	0.035	1.211 (0.611–2.403)	0.583	
CI, confidence interval; HR, hazard ratio.

Table 5 Univariate and multivariate analyses of disease-free survival of patients with pT4bN0M0 colorectal cancer.

	Disease-free survival	
	Univariable analysis	Multivariate analysis	
Variables	HR (95% CI)	P	HR (95% CI)	P	
Age (≥60/<60 years)	1.834 (1.111–3.026)	0.018	1.869 (1.116–3.131)	0.017	
Gender (female/male)	1.498 (0.928–2.420)	0.098	0.644 (0.277–1.496)	0.306	
BMI (≥24/<24 kg/m2)	1.238 (0.741–2.071)	0.415			
Hb (≥120/<120 g/l)	1.143 (0.705–1.854)	0.588			
Alb (≥40/<40 g/l)	1.097 (0.658–1.832)	0.722			
Smoking history (yes/no)	0.813 (0.451–1.468)	0.493			
Pulmonary function (abnormal/normal)	1.106 (0.684–1.789)	0.681			
Operation date (2016–2021/2010–2015)	0.838 (0.509–1.380)	0.487			
Concomitant diseases (yes/no)	1.312 (0.807–2.133)	0.273			
Complications at diagnosis (yes/no)	1.298 (0.740–2.277)	0.364			
CEA level (>5/≤5 ng/ml)	1.378 (0.849–2.234)	0.194	1.549 (0.924–2.595)	0.097	
CA19-9 level (>37/≤37 U/ml)	1.308 (0.746–2.296)	0.349			
Preoperative chemotherapy/radiotherapy (yes/no)	1.070 (0.627–1.824)	0.805			
Operative type (laparoscopic/open)	0.771 (0.461–1.287)	0.319			
Tumor location	
 Middle/lower rectum	—	—			
 Upper rectum/rectosigmoid junction	1.170 (0.636–2.151)	0.613			
 Colon	0.844 (0.463–1.536)	0.578			
Lymphovascular invasion (yes/no)	1.798 (0.882–3.663)	0.106	1.929 (0.912–4.078)	0.086	
Perineural invasion (yes/no)	1.218 (0.638–2.328)	0.550			
Tumor differentiation (poor/well-moderate)	1.520 (0.936–2.467)	0.090	1.422 (0.859–2.353)	0.171	
Tumor size (≥6/<6 cm)	0.662 (0.407–1.077)	0.096	0.732 (0.427–1.254)	0.256	
Type of organs invaded by CRC (gynecological system/nongynecological system)	2.069 (1.264–3.385)	0.004	2.827 (1.142–6.997)	0.025	
Number of organs invaded by CRC (two or more/one)	1.109 (0.632–1.946)	0.718			
Number of organ systems invaded by CRC (two or more/one)	2.014 (1.054–3.848)	0.034	1.463 (0.739–2.894)	0.275	
Number of organs invaded within the nongynecological system group (two or more/one)	0.876 (0.403–1.901)	0.737			
Number of organs invaded within the gynecological system group (two or more/one)	1.373 (0.594–3.174)	0.459			
Type of gynecological system organs invaded by CRC	
 Uterus	—	—			
 Ovary	1.098 (0.289–4.182)	0.890			
 Vagina	1.263 (0.386–4.130)	0.699			
 Two or more	1.370 (0.411–4.571)	0.608			
Medical centers	
 Center 1	—	—			
 Center 2	0.730 (0.433–1.232)	0.239			
 Center 3	0.774 (0.373–1.607)	0.492			
Postoperative adjuvant therapy (yes/no)	0.822 (0.487–1.389)	0.465			
Postoperative complications (yes/no)	0.788 (0.402–1.543)	0.487			
Alb, albumin; CA19-9, carbohydrate antigen 19-9; CEA, carcinoembryonic antigen; CI, confidence interval; CRC, colorectal cancer; Hb, hemoglobin; HR, hazard ratio.

Figure 4 Disease-free survival curves for pT4bN0M0 colorectal cancer patients with different ages.

Figure 5 Disease-free survival curves for pT4bN0M0 CRC patients with different types of organs invaded by CRC. CRC, colorectal cancer.

Development of the prognostic grading system

To stratify the survival of CRC patients with pT4bN0M0 disease, we classified the prognosis into different grades by utilizing the two independent prognostic factors: age and type of organs invaded by CRC. The patients were classified into three subgroups: low-risk, medium-risk, and high-risk groups. Accordingly, the low-risk group comprised patients with age <60 years and CRC invasion of the nongynecological organs, the medium-risk group comprised patients with age ≥60 years and CRC invasion of the nongynecological organs or age <60 years and CRC invasion of the gynecological organs, and the high-risk group comprised patients with age ≥60 years and CRC invasion of the gynecological organs. Cox proportional hazard analysis showed that the OS and DFS of the high-risk group (OS: HR=4.302; 95% CI=1.893–9.775; P<0.001; DFS: HR=3.713; 95% CI=1.816–7.591; P<0.001), as well as the medium-risk group (OS: HR=2.286; 95% CI=1.102–4.740; P=0.026; DFS: HR=2.076; 95% CI=1.118–3.857; P=0.021) were significantly poor as compared to those of the low-risk group (Tables 6 and 7). Furthermore, the OS and DFS of the high-risk group were significantly worse than those of the medium-risk group (OS: HR=1.905; 95% CI=0.995–3.647; P=0.052; DFS: HR=1.831; 95% CI=1.022–3.279; P=0.042). The OS and DFS curves for the different risk groups (P=0.001 and P=0.001, respectively) are depicted in Figures 6 and 7.

Table 6 Overall survival stratification analysis for the different risk grades.

Variables	HR (95% CI)	P	
Low-risk (age <60 and invasion of nongynecological organs)	—	—	
Medium-risk (age <60 and invasion of gynecological organs; age ≥60 and invasion of nongynecological organs)	2.286 (1.102–4.740)	0.026	
High-risk (age ≥60 and invasion of gynecological organs)	4.302 (1.893–9.775)	0.000	
CI, confidence interval; HR, hazard ratio.

Table 7 Disease-free survival stratification analysis for the different risk grades.

Variables	HR (95% CI)	P	
Low-risk (age <60 and invasion of nongynecological organs)	—	—	
Medium-risk (age <60 and invasion of gynecological organs; age ≥60 and invasion of nongynecological organs)	2.076 (1.118–3.857)	0.021	
High-risk (age ≥60 and invasion of gynecological organs)	3.713 (1.816–7.591)	0.000	
CI, confidence interval; HR, hazard ratio.

Figure 6 Overall survival curves for pT4bN0M0 colorectal cancer patients in different risk grades.

Figure 7 Disease-free survival curves for pT4bN0M0 colorectal cancer patients in different risk grades.

Discussion

The TNM staging system is a crucial guideline for determining the prognosis of CRC patients; hence, it needs to be constantly improved and updated with the latest findings from clinical practice. For example, CRC patients with stage IV disease show differential prognosis based on the location and number of metastatic organs12–16, and the current updated AJCC/TNM staging system has segregated stage IV CRC into IVB and IVC stages based on the number of distant metastases and peritoneal metastases. A similar issue has been observed for T4b stage CRC because of the complexity and diversity of tumor-infiltrated organs. The current clinical problem is that T4b patients with the same stage show apparent heterogeneity in their prognosis. Most previous studies on MVR for locally advanced CRC were single-center investigations with small sample data. The insufficient sample size limited the analysis of the sub-classification of pT4b stage, presently, there are no relevant studies on patients with pT4bN0M0 CRC to analyze the factors that influence the prognostic differences among patients with the same stage of CRC. In this context, a multicenter retrospective study was conducted to elucidate the prognostic factors of CRC patients with pT4bN0M0 disease. We found that the type of organs invaded by CRC was an independent factor that affected the OS and DFS of CRC patients with pT4bN0M0 disease. Additionally by using age and type of organs invaded by CRC as two independent prognostic factors, the patients were grouped into the low-risk, medium-risk, and high-risk groups. We found that the prognosis of these three groups differed significantly. We believe that the present study is the first to investigate whether the type of organs invaded by CRC is relevant for the prognostic stratification of patients with pT4bN0M0 CRC.

Some recent studies on MVR for locally advanced CRC have analyzed the effect of the number of organs removed on patient prognosis. However, it seems irrational to use the number of organs removed as a factor to classify the prognosis of patients with locally advanced CRC; this might be because an MVR study showed that only 55% of the tumors invaded the adjacent organs, while the remaining 45% tumors were inflammatory adhesions to the adjacent organs17. A previous study showed a significant difference in patient prognosis between tumor cell infiltration and inflammatory cell infiltration into the adjacent organs18. Therefore, strengthening the analysis of patients showing adjacent organ invasion by cancer cells can truly reflect the prognostic factors after MVR of locally advanced CRC. However, to date, few studies have elucidated how the type of organs invaded by CRC influences patient prognosis, and the relevance of this variable remains unclear. Wasmann et al. 19 analyzed the prognostic factors of overall locally advanced CRC; the results showed that the MVR of the abdominal wall/ovaries/omentum exhibited a significant relationship with intra-abdominal recurrence; in contrast, the multivariate survival analysis showed no significant difference in survival.

Different from the above-mentioned study, to minimize the effect of confounding factors and to identify the actual causes of prognostic differences in patients with the same stage of CRC, we assessed the prognostic factors of only patients with pT4bN0M0 CRC. To determine whether there are differences in the survival of different organ systems invaded by CRC, we compared the survival differences among the gynecological system, digestive system, and genitourinary system groups. We found that patients with cancer invasion of the digestive system and genitourinary system exhibited similar prognoses. However, the prognosis of patients with cancer invasion of the gynecological system was significantly worse than that of patients with cancer invasion of the digestive system or genitourinary system. Based on this result, we combined the digestive system and genitourinary system into the nongynecological system group, and other organs or structures were also included in the nongynecological system group due to the small number of cases. Finally, we divided the type of organs invaded by CRC into two groups: the gynecological system group and nongynecological system group. As shown by univariate and multivariate analyses, the prognosis of the gynecological system group was significantly worse than that of the nongynecological system group. Such a phenomenon might have several reasons. First, we found the proportion of postoperative recurrence and metastasis was higher in the gynecological system group. Second, the types of postoperative recurrence and metastasis were different between the two groups. The proportion of postoperative liver or lung metastasis in the nongynecological system group was higher than that in the gynecological system group (60% vs. 50%), while the proportion of postoperative peritoneal metastasis in the gynecological system group was higher than that in the nongynecological system group (19% vs. 8%). We think it might be related to biological behavior, which requires further basic research to clarify the specific molecular mechanism.

The present study has the following main advantages: it confirmed the presence of significant heterogeneity in survival among patients with pT4bN0M0 CRC and it showed that sub-classification of the type of organs invaded by CRC is an effective approach to identify prognostic differences among patients with pT4bN0M0, thus emphasizing that this variable is also critical for evaluating the prognosis of CRC patients with pT4bN0M0 disease. The prognostic relevance of the type of organs invaded by CRC is complementary to the current T4b staging. Therefore, based on our findings, we recommend that the T4b staging should include the type of organs invaded by CRC as a prognostic indicator. The inclusion of this variable as a new prognostic indicator in the T4b staging could enable optimize the classification of cancers with T4 staging and provide a critical reference value for the subsequent update of T4b staging.

Accurate prognostic assessment is crucial to manage cancer patients in clinical settings, and the development of a prognosis grading system helps to stratify the survival of patients. As reported earlier, patients with the same stage of cancer often exhibit differences in their prognosis20,21; a similar issue is observed in patients with pT4bN0M0 CRC. In previous studies, the construction of a prognostic scoring system enabled us to adequately stratify the prognosis of patients exhibiting the same cancer stage21–24. However, to date, there is no prognosis grading system for CRC patients with pT4bN0M0 stage disease. The present study revealed that, together with the type of organs invaded by CRC, age was also an independent factor that affected pT4bN0M0 patients’ survival, and elderly patients showed significantly worse prognoses than young patients. Previous studies have also supported the idea that age is a relevant prognostic factor for CRC patients25,26. To more accurately classify the prognostic differences among patients with pT4bN0M0 CRC, we performed a prognostic stratification analysis by using age and the type of organs invaded by CRC as the independent prognostic factors. On the basis of this analysis, we then classified the patients into three subgroups: high-risk, medium-risk, and low-risk groups. These three subgroups showed significant differences in prognosis. Elderly patients showing the gynecological organs invaded by CRC had the worst prognosis, while young patients showing the nongynecological organs invaded by CRC exhibited the best prognosis. Prognostic stratification analysis revealed that age combined with the type of organs invaded by CRC could more accurately stratify the prognosis of CRC patients with pT4bN0M0 disease. Therefore, we suggest avoiding the generalization of the prognosis of CRC patients with pT4bN0M0 disease in clinical practice; furthermore, the classification of prognostic grades can enable to predict the survival of CRC patients with pT4bN0M0 disease individually.

The limitations of the present study should be acknowledged. First, the retrospective nature of our study is an inherent limitation. Second, because the sample size of patients was small, we only classified organs invaded by CRC according to the organ system and did not conduct a detailed analysis of whether prognostic differences existed for each organ invaded by CRC. This limited our in-depth study of the invasion of the organs by CRC to a certain extent. We believe that future multicenter and large-scale prospective studies on the organs affected by CRC invasion could provide more evidence-based medical evidence. Although there are some limitations, our study has two valuable aspects: prognostic stratification of CRC patients with pT4bN0M0 disease and the development of a new prognostic indicator for these patients.

Conclusions

Our study confirmed that the type of organs invaded by CRC is a valuable prognostic indicator that can identify survival differences among patients with pT4bN0M0 CRC. We also performed a prognostic stratification analysis by using the independent prognostic factors of age and the type of organs invaded by CRC, which can more accurately stratify the prognosis of CRC patients with pT4bN0M0 disease.

Ethical approval

The Ethics Committee of the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College approved this study (NCC-010289).

Consent

Institutional Review Boards waived informed consent requirement because this was a retrospective study.

Sources of funding

This work is supported by the Wu Jieping’s Foundation Special for Clinical Research (Grant Number: 320.6750.2021–04-02); Beijing Natural Science Foundation (Grant Numbers: L222054 and 4232058); Special Research Fund for Central Universities, Peking Union Medical College (Grant Number: 3332022092); and Administrative Research Fund, CHCAMS (Grant Number: LC2021D10).

Author contribution

J.Q.: conceptualization, methodology, data curation, formal analysis, and writing-original draft. K.Z., G.L.: methodology, data curation, formal analysis, and writing-original draft. J.L., S.M., G.H., W.Q., M.Z., L.M.: data curation, visualization, and investigation. X.W., H.C., J.T.: conceptualization, supervision, writing review, and editing. All authors made critical revisions to the manuscript and approved the final manuscript.

Conflicts of interest disclosure

There are no conflicts of interest.

Research registration unique identifying number (UIN)

Name of the registry: ClinicalTrials. gov.

Unique identifying number or registration ID: NCT06115837.

Hyperlink to your specific registration (must be publicly accessible and will be checked): https://clinicaltrials.gov/study/NCT06115837.

Guarantor

Jianqiang Tang.

Data availability statement

The datasets used during the current study are available from the corresponding author upon reasonable request.

Provenance and peer review

Not commissioned, externally peer-reviewed.

J.Q., K.Z., and G.L.: contributed equally to this study.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Published online 20 May 2024
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