Abstract
High-level evidence on the long-term efficacy of postoperative TME quality in patients with low rectal cancer is lacking. The LASRE trial was used as background data to further explore the impact of TME quality on overall survival. We carried out a secondary analysis of the LASRE trial, which prospectively enrolled patients less than 5 cm from the dentate line from 22 hospitals in China who had undergone total mesorectal resection. TME quality was classified into 3 grades: grade A (complete), grade B (nearly complete), and grade C (incomplete), which were independently judged by the pathologist and surgeon, respectively, and if the results were inconsistent, then a third party finalized the grading based on photos of the specimen. 921 patients were included in the analysis, 787 (85.5%) in grade A, 108 (11.7%) in grade B, and 26 (2.8%) in grade C. The median follow-up was 36.0 months, and Kaplan-Meier curves showed that 3-year OS before PSM matching was 93.2% for grade A, 84.3% for grade B, 88.5% for grade C (P=0.0038), and 85.1% for grade B/C (P=0.0011). After PSM, it was 92.5% for grade A and 86.8% for grade B/C (P=0.044). TME quality was an independent influence on overall survival before PSM matching (HR=1.691, 95% CI: 1.133~2.522, p=0.010), and after PSM matching, TME quality remained an independent factor for OS (HR=1.881, 95% CI: 1.035~3.416, p=0.038). Excellent TME quality after surgery for low rectal cancer contributes to an improved prognosis and is an independent factor influencing long-term outcome.
Keywords: Total mesorectal excision quality, TME quality, Overall survival, Low rectal cancer, LASRE trial
Subject terms: Cancer, Gastroenterology, Medical research, Oncology
Introduction
Since the 1980s, Professor Heald proposed the principle of total mesorectal excision (TME), which has become the gold standard for radical surgery of rectal cancer, resulting in a significant decrease in the local recurrence rate of rectal cancer1,2. Research has shown that TME reduces the local recurrence rate of rectal cancer to less than 10% after surgery and increases the disease-free survival (DFS) rate to more than 70%3. One study suggested that the correct or incorrect intraoperative plane of operation according to the principles of TME is an important prognostic factor for local recurrence, but the impact on long-term prognosis has not been further confirmed4.
TME quality was classified into 3 different grades (mesorectal, intramesorectal, and muscularis propria plane) based on postoperative specimen integrity5. In a large population-based retrospective study of low to intermediate rectal cancer, it was concluded that poorer TME quality increased the risk of local recurrence but did not appear to affect distant recurrence or survival6. Owing to ethical constraints, it would be unethical to design a prospective, randomised controlled trial (RCT) with a primary focus on TME quality, and therefore the current studies are mostly retrospective and have relatively small sample sizes7–9. There may not even be relevant RCT studies in the future. Similarly, in the well-known CAO/ARO/AIO-04 study, although a secondary analysis of TME quality was also performed and confirmed to be associated with postoperative local recurrence, but this study mainly focused on patients with locally progressive rectal cancer within 12 cm from the anus, and the population was relatively limited5,10.
Low rectal cancer (within 5 cm from the dentate line) is more difficult to operate in the presence of narrow pelvic operating space, and according to the principle of TME and the requirement of removing all rectal mesentery, in addition to safeguarding postoperative anal and sexual function, so previous studies concluded that the risk of incomplete TME and positive circumferential margins for low rectal cancer is higher, regardless of the use of laparoscopic or open surgery11. Presently, high-level evidence on the long-term efficacy of TME quality after surgery for low rectal cancer patients is still lacking. LASRE was a multicenter, randomised, controlled, non-inferiority trial designed to compare the safety and efficacy of laparoscopic or open surgery for the treatment of low rectal cancer. As a high-quality study, it included a total of 1070 participants between 2013 and 2018 to prospectively assess the quality of TME, and the main findings of the related study have been published online12,13. Thus, with the aim of further exploring the impact of TME quality on overall survival, this study used LASRE as a secondary analysis of background data.
Methods
Study design
This study is a secondary analysis of the LASRE trial, which prospectively enrolled patients with low rectal cancer less than 5 cm from the dentate line in 22 hospitals in China. All patients were randomised to laparoscopic or open surgery in a 2:1 ratio after enrolment, and all operations had undergone resection of the entire rectal mesentery according to the principle of complete TME. The trial protocol was approved by the ethics committees of all participating centers and informed consent was obtained from each patient. It was registered at ClinicalTrials.gov with identifier NCT0189954712,13. In this study, missing information on the TME quality was mainly excluded, in addition to distant metastases, upper rectal cancer, refused surgery, non-rectal cancer, local resection (Fig. 1).
Fig. 1.
Study flow.
Treatment
Patients with locally advanced rectal cancer (clinical stage II/III) underwent preoperative neoadjuvant CRT All patients received concurrent radiotherapy and concurrent oral fluorouracil chemotherapy during radiotherapy. The radiotherapy dose was 45.0 ~ 50.4 Gy in 25 ~ 28 sessions. Stage II/III patients received additional preoperative capecitabine chemotherapy (1250 mg/m2 twice daily for 2 weeks) after radiotherapy and before surgery. No patients underwent total neoadjuvant therapy (TNT) before surgery. Adjuvant chemotherapy should be continued postoperatively, using oral regimens such as CapeOx (oxaliplatin plus capecitabine) or capecitabine alone. Perioperative chemotherapy should not exceed 6 months.
Surgery was performed after a median time interval of 6-8 weeks after radiotherapy. Perioperative procedures and surgical principles were the same in both groups, except for different surgical access, all of them removed the entire rectal mesentery according to the TME principle.
Evaluation standards for the quality of TME14
Grade A (complete): rectal mesentery with sufficient volume and smooth surface, only slight irregular defects on the rectal mesentery surface, and no defects >5mm in depth on both the stripped surface of the rectal mesentery and the plasma membrane surface (Fig. 2).
Fig. 2.
TME image of typical Grade A.
Grade B (nearly complete): the rectal mesentery is of moderate volume, the surface of the rectal mesentery is irregular, and the defect is >5 mm, but it does not extend to the intrinsic muscular layer, and the intrinsic muscular layer is not visible on the peeled surface of the rectal mesentery, except for the anorectal muscles.
Grade C (incomplete): small rectal mesentery volume, rectal mesentery surface defect deep to the intrinsic muscle layer, irregular peripheral cut margins in the posterior circumference of the rectal mesentery in transverse section, and local cut margins formed by the intrinsic muscle layer.
The TME quality was judged independently by the pathologist and the surgeon, respectively, as described above, and if the results were inconsistent, a third person made the final determination of grading based on photos of the specimen.
Follow-up
Each patient is followed up regularly after surgery, every 3 months in the first 2 years and every 6 months in the second 3 years. Follow-up methods: outpatient, telephone, and correspondence by specialized postoperative colorectal cancer follow-up staff. Unless patients died or were lost to follow-up, the study was followed up to 3 years postoperatively. OS was defined as the time from the start of randomization to death from any cause.
Statistical analysis
PSM matched using logistic regression to estimate each patient’s propensity score, to reduce selection bias between the two groups15. For the convenience of PSM matching, we classified Grade B and C into the same group (Grade B/C) for PSM analyses. Logistic regression models included the following variables: age, sex, BMI, ASA score, carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9), distance to the anal verge, surgery method, sphincter preservation, nCRT, central group lymph node status, pT/N/TNM stage. grade B/C patients were matched 1:4 per case to grade A patients (caliper=0.2). PSM matching was performed using SPSS 29 (IBM SPSS Statistics, Chicago, IL, USA).
Clinicopathological characteristics were compared between groups before and after PSM. The chi-square test or Fisher’s exact test was used for categorical variables, and the rank-sum test was used for ordinal variables. The data met normality, and continuous data were compared using the Student’s t-test (data expressed as mean ± standard deviation). Survival outcomes were analyzed and compared using the Kaplan-Meier method. Multifactorial analysis was performed using Cox proportional risk regression (HR). P-value <0.05 was considered statistically significant.
Results
921 patients with low rectal cancer were included in the study, of which 787 (85.5%) were grade A, 108 (11.7%) were grade B, and 26 (2.8%) were grade C.
Patient characteristics
Baseline characteristics are shown in Table 1. Before PSM, there were significant differences between the three groups of patients in terms of distance to the anal verge and sphincter preservation. To further reduce bias due to confounding factors, 408 (76.0%) were class A and 129 (24.0%) were class B/C after PSM matching. The factors were well matched for better comparability (Table 1).
Table 1.
Characteristics of patients in different groups according to total mesorectal excision (TME) quality.
| Variables | Before PSM | After PSM | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Grade A | Grade B | Grade C | P | *Grade B/C | P | Grade A | Grade B/C | P | |
| Sex | 0.332 | 0.688 | 0.852 | ||||||
| Female | 311 (60.5) | 42 (38.9) | 14 (53.8) | 56 (58.2) | 167 (40.9) | 54 (41.9) | |||
| Male | 476 (39.5) | 66 (61.1) | 12 (46.2) | 78 (41.8) | 241 (59.1) | 75 (58.1) | |||
| Age (years) | 0.348 | 0.175 | 0.173 | ||||||
| ≤60 | 481 (61.1) | 59 (54.6) | 14 (53.8) | 73 (54.5) | 249 (61.0) | 70 (54.3) | |||
| >60 | 306 (38.9) | 49 (45.4) | 12 (46.2) | 61 (45.5) | 159 (39.0) | 59 (45.7) | |||
| BMI (kg/m2) | 0.656 | 1.000 | 0.516 | ||||||
| ≤25 | 596 (75.7) | 84 (77.8) | 18 (69.2) | 102 (76.1) | 318 (77.9) | 97 (75.2) | |||
| >25 | 191 (24.3) | 24 (22.2) | 8 (30.8) | 32 (23.9) | 90 (22.1) | 32 (24.8) | |||
| ASA score | 0.158 | 0.226 | 0.270 | ||||||
| I | 563 (71.5) | 75 (69.4) | 14 (53.8) | 89 (66.4) | 293 (71.8) | 86 (66.7) | |||
| II | 215 (27.3) | 31 (28.7) | 12 (46.2) | 43 (32.1) | 109 (26.7) | 41 (31.8) | |||
| III | 9 (1.1) | 2 (1.9) | 0 (0.0) | 2 (1.5) | 6 (1.5) | 2 (1.6) | |||
| CA19-9 (U/ml) | 0.388 | 1.000 | 1.000 | ||||||
| ≤37 | 760 (96.6) | 105 (94.2) | 24 (92.3) | 129 (96.3) | 392 (96.1) | 124 (96.1) | |||
| >37 | 27 (3.4) | 3 (2.8) | 2 (7.7) | 5 (3.7) | 16 (3.9) | 5 (3.9) | |||
| CEA (ng/ml) | 0.185 | 0.426 | 0.712 | ||||||
| ≤5 | 676 (85.9) | 92 (85.2) | 19 (73.1) | 111 (82.8) | 344 (84.3) | 107 (82.9) | |||
| >5 | 111 (14.1) | 16 (14.8) | 7 (26.9) | 23 (17.2) | 64 (15.7) | 22 (17.1) | |||
| Distance to the anal verge (mm) | 50.7±15.9 | 43.7±15.1 | 43.9±15.5 | <0.001 | 43.7±15.3 | <0.001 | 46.9±16.9 | 44.3±15.1 | 0.158 |
| Surgery method | 0.777 | 0.905 | 0.550 | ||||||
| Laparoscopic | 521 (66.2) | 74 (68.5) | 16 (61.5) | 90 (67.2) | 257 (63.0) | 85 (65.9) | |||
| Open | 266 (33.8) | 34 (31.5) | 10 (38.5) | 44 (32.8) | 151 (37.0) | 44 (34.0) | |||
| Sphincter preservation | <0.001 | <0.001 | 0.055 | ||||||
| Yes | 602 (76.5) | 47 (43.5) | 12 (46.2) | 59 (44.0) | 226 (55.4) | 59 (45.7) | |||
| No | 185 (23.5) | 61 (56.5) | 14 (53.8) | 75 (56.0) | 182 (44.6) | 70 (54.3) | |||
| nCRT | 0.691 | 0.494 | 0.473 | ||||||
| Yes | 525 (66.7) | 75 (69.4) | 19 (73.1) | 94 (70.1) | 274 (67.2) | 91 (70.5) | |||
| No | 262 (33.3) | 33 (30.6) | 7 (26.9) | 40 (29.9) | 134 (32.8) | 38 (29.5) | |||
| Central group lymph node status | 0.458 | 0.626 | 0.676 | ||||||
| Negative | 780 (99.1) | 106 (98.1) | 26 (100.0) | 132 (98.5) | 403 (98.8) | 127 (98.4) | |||
| Positive | 7 (0.9) | 2 (1.9) | 0 (0.0) | 2 (1.5) | 5 (1.2) | 2 (1.6) | |||
| pT stage | 0.423 | 0.426 | 0.662 | ||||||
| T0/Tis | 116 (14.7) | 13 (12.0) | 5 (19.2) | 18 (13.4) | 61 (15.0) | 17 (13.2) | |||
| T1 | 77 (9.8) | 6 (5.6) | 1 (3.8) | 7 (5.2) | 31 (7.6) | 7 (5.4) | |||
| T2 | 267 (33.9) | 41 (38.0) | 11 (42.3) | 52 (38.8) | 147 (36.0) | 52 (40.3) | |||
| T3 | 284 (36.1) | 40 (37.0) | 8 (30.8) | 48 (35.8) | 149 (36.5) | 45 (34.9) | |||
| T4 | 43 (5.5) | 8 (7.4) | 1 (3.8) | 9 (6.7) | 20 (4.9) | 8 (6.2) | |||
| pN stage | 0.274 | 0.179 | 0.748 | ||||||
| N0 | 595 (75.6) | 74 (68.5) | 20 (76.9) | 94 (70.1) | 300 (73.5) | 93 (72.1) | |||
| N+ | 192 (24.4) | 34 (31.5) | 6 (23.1) | 40 (29.9) | 108 (26.5) | 36 (27.9) | |||
| pTNM stage | 0.391 | 0.254 | 0.711 | ||||||
| 0 | 112 (14.2) | 12 (11.1) | 4 (15.4) | 16 (11.9) | 57 (14.0) | 16 (12.4) | |||
| I | 278 (35.3) | 37 (34.3) | 9 (34.6) | 46 (34.3) | 143 (35.0) | 46 (35.7) | |||
| II | 205 (26.0) | 25 (23.1) | 7 (26.9) | 32 (23.9) | 100 (24.5) | 31 (24.0) | |||
| III | 192 (24.4) | 34 (31.5) | 6 (23.1) | 40 (29.9) | 108 (26.5) | 36 (27.9) | |||
*Compare with Grade A.
Abbreviations: BMI, body mass index; ASA, American Society of Anesthesiologists Score; CEA, circumferential resection margin; CA19-9, carbohydrate antigen 19-9; nCRT, neoadjuvant chemoradiotherapy.
Survival outcomes
The median follow-up was 36.0 months (interquartile range 0.8 to 36 months). A total of 73 patient deaths were followed up, including 68 deaths due to rectal cancer metastasis, 3 deaths due to trauma, 1 death due to primary esophageal cancer, and 1 death due to primary liver cancer. Kaplan-Meier curves showed that OS at the 3 years before PSM was 93.2% for Grade A, 84.3% for Grade B, 88.5% for Grade C (P=0.0038), and 85.1% for Grade B/C (P=0.0011). After PSM was 92.5% for Grade A, 86.8% for Grade B/C (P=0.044) (Fig. 3).
Fig. 3.
Kaplan-Meier curve of overall survival according to TME quality before PSM (A, B) and after PSM (C).
Independent prognostic Factors
We further examined the role of TME quality on 3-year OS in a Cox model. multivariate Cox regression analysis of OS before PSM is shown in Table 2, TME quality had an independent effect (HR=1.691, 95% CI: 1.133~2.522, p=0.010), in addition to Gender, CA19-9, Distance to the anal verge, Neoadjuvant chemoradiotherapy, central group lymph nodes status, pT stage, pN stage were all independent factors (Table 2).
Table 2.
Univariate and multivariate Cox regression analyses associated of factors with 3-year OS before PSM (n=921).
| Variables | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| TME quality (Grade C, Grade B vs. Grade A) | 1.702 (1.114~2.600) | 0.014 | 1.691 (1.133~2.522) | 0.010 |
| Surgery method (Laparoscopic vs. Open) | 1.506 (0.884~2.565) | 0.132 | ||
| Gender (Female vs. Male) | 0.589 (0.346~1.002) | 0.051 | 0.583 (0.344~0.987) | 0.045 |
| Age (>60 vs. ≤60 years) | 1.329 (0.827~2.136) | 0.240 | ||
| BMI (>25 vs. ≤25 kg/m2) | 0.925 (0.524~1.633) | 0.788 | ||
| ASA score ((III, II vs. I) | 1.008 (0.622~1.634) | 0.975 | ||
| CEA (>5 vs. ≤5 ng/ml) | 1.307 (0.729~2.341) | 0.368 | ||
| CA19-9 (>37 vs. ≤37 U/ml) | 2.289 (0.906~5.782) | 0.080 | 2.510 (1.044~6.035) | 0.040 |
| Distance to the anal verge (mm) | 0.981 (0.965~0.999) | 0.033 | 0.982 (0.968~0.996) | 0.013 |
| Neoadjuvant chemoradiotherapy (Yes vs. No) | 1.967 (1.100~3.520) | 0.023 | 1.863 (1.054~3.290) | 0.032 |
| Sphincter preservation (Yes vs. No) | 1.059 (0.577~1.941) | 0.854 | ||
| Central group lymph nodes status (Positive vs. Negative) | 2.579 (0.826~8.051) | 0.103 | 3.010 (1.001~9.053) | 0.050 |
| pT stage (T4, T3, T2, T1 vs. T0/Tis) | 1.731 (1.115~2.687) | 0.014 | 1.356 (1.055~1.742) | 0.017 |
| pN stage (N+ vs. N0) | 5.610 (1.595~19.734) | 0.007 | 2.359 (1.441~3.862) | 0.001 |
| pTNM stage (III, II, I vs. 0) | 0.543 (0.239~1.235) | 0.145 | ||
Abbreviations: PSM, propensity-score matching; OS, overall survival; BMI, body mass index; ASA, American Society of Anesthesiologists Score; CEA, circumferential resection margin; CA19-9, carbohydrate antigen 19-9.
After adjusting the classification according to TME quality, Cox regression showed that TME quality remained an independent factor on OS (HR=2.114, 95% CI: 1.252~3.568, p=0.005) (Table 3).
Table 3.
Univariate and multivariate Cox regression analyses associated of factors with 3-year OS before PSM (n=921).
| Variables | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| TME quality (Grade B/C vs. Grade A) | 2.096 (1.213~3.624) | 0.008 | 2.114 (1.252~3.568) | 0.005 |
| Surgery method (Laparoscopic vs. Open) | 1.473 (0.865~2.509) | 0.154 | ||
| Gender (Female vs. Male) | 0.592 (0.349~1.007) | 0.053 | 0.589 (0.348~0.998) | 0.049 |
| Age (>60 vs. ≤60 years) | 1.318 (0.819~2.119) | 0.255 | ||
| BMI (>25 vs. ≤25 kg/m2) | 0.949 (0.537~1.678) | 0.857 | ||
| ASA score ((III, II vs. I) | 1.009 (0.623~1.634) | 0.971 | ||
| CEA (>5 vs. ≤5 ng/ml) | 1.329 (0.744~2.371) | 0.336 | ||
| CA19-9 (>37 vs. ≤37 U/ml) | 2.333 (0.927~5.869) | 0.072 | 2.568 (1.070~6.160) | 0.035 |
| Distance to the anal verge (mm) | 0.981 (0.964~0.998) | 0.033 | 0.982 (0.968~0.997) | 0.016 |
| Neoadjuvant chemoradiotherapy (Yes vs. No) | 1.962 (1.097~3.507) | 0.023 | 1.868 (1.057~3.300) | 0.031 |
| Sphincter preservation (Yes vs. No) | 1.081 (0.588~1.988) | 0.801 | ||
| Central group lymph nodes status (Positive vs. Negative) | 2.597 (0.834~8.085) | 0.100 | 3.017 (1.006~9.041) | 0.049 |
| pT stage (T4, T3, T2, T1 vs. T0/Tis) | 1.722 (1.109~2.675) | 0.015 | 1.361 (1.059~1.750) | 0.016 |
| pN stage (N+ vs. N0) | 5.345 (1.520~18.787) | 0.009 | 2.316 (1.415~3.790) | 0.001 |
| pTNM stage (III, II, I vs. 0) | 0.553 (0.243~1.259) | 0.158 | ||
Abbreviations: PSM, propensity-score matching; OS, overall survival; BMI, body mass index; ASA, American Society of Anesthesiologists Score; CEA, circumferential resection margin; CA19-9, carbohydrate antigen 19-9.
After PSM matching, the associated independent factors were reduced, yet TME quality remained an independent factor on OS (HR=1.881, 95% CI: 1.035~3.416, p=0.038) (Table 4).
Table 4.
Univariate and multivariate Cox regression analyses associated of factors with 3-year OS after PSM (n=537).
| Variables | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| TME quality (Grade B/C vs. Grade A) | 1.862 (1.012~3.427) | 0.046 | 1.881 (1.035~3.416) | 0.038 |
| Surgery method (Laparoscopic vs. Open) | 1.371 (0.720~2.610) | 0.336 | ||
| Gender (Female vs. Male) | 0.814 (0.432~1.535) | 0.526 | ||
| Age (>60 vs. ≤60 years) | 1.350 (0.739~2.466) | 0.329 | ||
| BMI (>25 vs. ≤25 kg/m2) | 0.862 (0.402~1.847) | 0.702 | ||
| ASA score ((III, II vs. I) | 0.747 (0.394~1.418) | 0.373 | ||
| CEA (>5 vs. ≤5 ng/ml) | 1.344 (0.660~2.736) | 0.415 | ||
| CA19-9 (>37 vs. ≤37 U/ml) | 2.802 (0.982~7.992) | 0.054 | 2.769 (1.060~7.235) | 0.038 |
| Distance to the anal verge (mm) | 0.986 (0.965~1.008) | 0.201 | ||
| Neoadjuvant chemoradiotherapy (Yes vs. No) | 2.231 (1.059~4.701) | 0.035 | ||
| Sphincter preservation (Yes vs. No) | 1.070 (0.522~2.191) | 0.854 | ||
| Central group lymph nodes status (Positive vs. Negative) | 3.118 (0.912~10.665) | 0.070 | 4.324 (1.420~13.167) | 0.010 |
| pT stage (T4, T3, T2, T1 vs. T0/Tis) | 1.558 (0.905~2.683) | 0.110 | ||
| pN stage (N+ vs. N0) | 4.763 (0.948~23.921) | 0.058 | 2.372 (1.299~4.330) | 0.005 |
| pTNM stage (III, II, I vs. 0) | 0.591 (0.214~1.637) | 0.312 | ||
Abbreviations: PSM, propensity-score matching; OS, overall survival; BMI, body mass index; ASA, American Society of Anesthesiologists Score; CEA, circumferential resection margin; CA19-9, carbohydrate antigen 19-9.
Discussion
According to the principles of TME, extensive mesorectal excision (removal of at least 5 cm of the mesorectal at the lower edge of the tumour) is performed for high-grade rectal cancer, whereas complete TME, with removal of the entire mesorectal, is required for low- and intermediate-grade rectal cancer4. In our study, 85.5% of TME quality assessments achieved grade A, which is similar to some current studies and guarantees postoperative efficacy5,6. There was a significant difference in long-term survival for all different TME qualities, which was confirmed by multivariate regression as an independent influence on long-term overall survival.
Laparoscopic technique has been widely used in rectal cancer due to its advantages of being minimally invasive and rapid postoperative recovery16. A Meta-analysis that included 4034 patients and compared the TME quality after open and laparoscopic surgery for rectal cancer concluded that there was a higher percentage of laparoscopic group in near complete and incomplete mesorectal resections as compared to open surgery, and the difference between the two groups was statistically significant (13.2% vs. 10.4%, RR = 1.31, P = 0.02)17. These findings question the oncological safety of laparoscopic treatment of rectal cancer. Nevertheless, the subsequent long-term results in our lead LASRE randomised controlled trial have confirmed that the 3-year overall survival rate of laparoscopic surgery for low rectal cancer is not lower than that of open surgery (HR = 1.34, 95% CI 0.82 ~ 2.19; p = 0.24), which is consistent with the results of the present secondary analysis13. With similar results, a large multicenter cohort study from 69 institutes collected a total of 1,608 cases with anal margin tumours of 4.6 cm for analysis, and the proportion of anal preservation was higher in the laparoscopic group than in the open group (60.0% vs. 53.3%, p = 0.037), and laparoscopic surgery can be considered an effective option for low rectal cancer and offers a minimally invasive alternative to sphincter preservation18. This result can be explained by the fact that in laparoscopic surgery, due to the use of a laparoscope, the narrow pelvic space, it projects a magnified and well-illuminated image of the surgical field on the monitor. A clear field of view seems to be more conducive to complete tumour resection with adequate margins. In the present study, the TME quality was non-significantly different between the two groups of patients.
We found in our study that patients with poorer TME quality tended to have tumours lower from the anus and a lower rate of sphincter preservation. Previous studies have supported this finding by suggesting that the lower the position from the anus the significantly more difficult the surgery would be19,20. Mesorectal fat area (MFA) assessment by preoperative magnetic resonance can assist in predicting surgical difficulty, with greater MFA area limiting operation within a narrow pelvic space and increasing the difficulty of visual field exposure, with the above reasons indirectly contributing to a reduction in the quality of the TME20. However, the use of robotic surgical systems in low rectal cancer surgery can help to improve the TME quality by overcoming the limitations of conventional surgery in the pelvis, reducing surgical trauma and complications through the advantages of its high-definition 3D vision system, flexible robotic arm, and precise suturing and reconstruction tools, especially when dealing with obese or male patients, or patients with pelvic stenosis.21.
Previously LASRE disclosed a 69.4% rate of sphincter preservation in low rectal cancer12. In our post hoc analysis, which included only patients with low rectal cancer after neoadjuvant therapy, the proportion of sphincter preservation slightly increased to 71.9%, and the SSPR rate varied significantly from hospital to hospital, ranging from 37.7% to 94.4%22. Studies have shown that preoperative neoadjuvant therapy helps to reduce local tumour stage and increase the probability of sphincter preservation, but nCRT leads to postoperative tissue alterations such as fibrosis, oedema, fatty degeneration, and necrosis, which may result in unclear anatomical dimensions, surgery operated in the wrong plane, and reduced TME quality (OR= 2.056, p = 0.017)7.
This study still has some limitations. Firstly, low rectal cancer surgery is a challenging surgical procedure, and although the participating surgeons were experienced in colorectal surgery, the subjectivity of TME quality assessment may vary slightly in different centers, and we reduced the variation by using independent judgement of pathologists and surgeons. Second, we excluded patients with missing TME quality information from the post hoc analyses, which may have overestimated or underestimated the results, and for historical reasons we had to acknowledge that some of the postoperative specimens had missing photos and could not be evaluated secondary. Finally, as a secondary analysis, TME quality was not the primary study endpoint of LASRE, and although a prospective evaluation was performed, a small number of differences in baseline characteristics between groups still existed, especially in the two characteristics of distance to the anal verge and sphincter preservation, and the PSM analysis method helped us to overcome this point in order to try to achieve the randomised analogue state, but it also had to lead to a reduced sample size.
Conclusion
Excellent TME quality after surgery for low rectal cancer contributes to an improved prognosis and is an independent factor influencing long-term outcome. Surgery should be performed following the principles of TME, and the correct plane of operation maintained, especially after neoadjuvant therapy.
Acknowledgments
We would like to express our sincere gratitude to the patients, investigators, and various central hospitals that contributed to the successful conduct of this study.
Author contributions
Protocol/Project Development: GW, KY, WY, YG; Data Collection/Management: GW, KY, WY; Data Analysis: WJ, PC, YH; TME quality review: KY, WY; Manuscript Writing/Editing: GW.
Funding
This study was supported by the Natural Science Foundation of Fujian Province (grant no. 2023J011819).
Data availability
All data obtained or analyzed during this study are included in the article.
Declarations
Competing interests
The authors declare no competing interests.
Ethics
This study was reviewed and approved by the central ethics committees of Fujian Medical University Union Hospital (Approval No. 2013051 for LASRE trial). All methods were performed in accordance with relevant guidelines and regulations, including the Declaration of Helsinki. Informed consent was obtained from all subjects and/or their legal guardians (s) for this study.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Guancong Wang, Kaining Ye, and Weiping Yang contributed equally and should be considered co-first authors. All authors have reviewed the manuscript.
Contributor Information
Weizhong Jiang, Email: jiangwz362100@163.com.
Pan Chi, Email: chipan363@163.com.
Ying Huang, Email: fjxhhy@sina.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data obtained or analyzed during this study are included in the article.