3.3 Correlation between the EMD/mesorectum ratio and patient characteristics
Of the 287 patients, 124 (43.2%) had a EMD/mesorectum ratio < 0.3. The correlation between the EM/mesorectum ratio and patient characteristics was shown in Table 2. A EMD/mesorectum ratio ≥ 0.3 occurred more often in patients with BMI < 25. Patients with serum CEA level ≥ 5 ng/mL, tumor size on MRI ≥ 5 cm, tumor on anterior rectal wall, MR-LN positive and positive MRF, patients with positive EMVI also had higher proportion of EMD/mesorectum ratio ≥ 0.3. Patients with EMD/mesorectum ratio ≥ 0.3 also had higher combined resection rate and lower rate of anus-conserving surgery. For the postoperative pathological findings, patients with pathological lymph node invasion had a higher proportion of EMD mesorectum ratio ≥ 0.3.
3.4 Independent prognostic factors for survival
The results of univariate and multivariate analysis are shown in Table 3. In the univariate analysis of RFS, tumor size on MRI, EMD/mesorectum ratio, MR-LN status, EMVI, surgical approach, TNM stage after operation, venous invasion and neural invasion were associated with DFS. For OS, both patients undergone abdominoperineal resection (APR) and hartmann surgery and patients with Tumor size ≥ 5 cm, MR-LN positive, EMVI positive and venous invasion all had decreased OS (Table 3A). A Cox multivariate analysis was performed for variables with P < .05 in the univariate analysis. The multivariate analysis showed that EMD/mesorectum ratio ≥ 0.3 (HR 2.038; 95% CI: 1.230–4.123; P = .032) was the only preoperative independent adverse prognostic factor for RFS. For OS, the independent prognostic risk factors were MR-LN positive (HR 2.551; 95% CI 1.079–6.030; P = .033) and surgical approach (HR 3.025; 95% CI 1.346–6.797; P = .007) (Table 3B).
3.5 Survival analysis
The 5-year RFS and OS rate of patients with EMD/mesorectum ratio ≥ 0.3 were 70.4% and 82.1%, respectively, which were significantly worse than those of EMD/mesorectum ratio < 0.3 (88.0% and 92.2%) (HR: 3.068, 95% CI: 1.540–4.634, P < .001; HR: 2.591, 95% CI: 1.068–5.031, P = .034) (Fig. 4A and B). Furthermore, we analyzed the association between RFS rate of patients with EMD/mesorectum ratio ≥ 0.3 and nCRT. Of the 163 patients with EMD/mesorectum ratio ≥ 0.3, 61 patients had undergone nCRT with different intensity, and the baseline characteristics of the 2 groups are comparable (Table 4). Patients who undergone nCRT had higher 5-year RFS compared with patients without nCRT [86.9% vs 63.2%, HR 2.652; 95% CI: 1.229–4.357; P = .001 (Fig. 5)].
An accurate staging system to classify patients into relatively homogeneous groups according to their prognosis is crucial, because these classifications enable clinicians to provide personalized treatment strategy or adequate surveillance to patients. The depth of infiltration of primary tumor (T classification), nodal status (N classification), lymphovascular invasion, perineural invasion, and preoperative carcinoembryonic antigen level were found to have prognostic impact in multiple trials. An important aim of the present work was to evaluate the value of the EMD/mesorectum ratio as a maker of T3 subclassification in the T3 mid-low rectal cancer. To the best of our knowledge, this is the first report with such a large sample, describing the impact of EMD/mesorectum ratio, clinicopathologic, and radiologic factors on the prognosis.
The prognostic significance of the pathlogical EMD in rectal cancer was showed in many reports,[1,3,4,18–22] and the cutoff value of the EMD using to predict survival was range from 2 to 15 mm. Moreover, previous studies[9–11] had demonstrated the EMD detected by MRI was an independent prognostic factor. Cho et al confirmed that the EMD detected by MRI was an independent prognostic factor in patients with T3 rectal cancer (HR: 2.186 95%CI: 1.336–3.577, P = .002), and the T3a (< 5 mm) patients had a higher 3-year DFS than T3b (5– 10 mm) and T3c (>10 mm) patients (P = .016, P = .0001, respectively). However, there were only 14 patients with T3c cancer in their study cohort of 146 patients, most tumors were T3a, and none of the patients had undergone nCRT which was unusual in currently clinical sets. Sueda et al described the impact of EMD and CRM on prognosis, and selected a value of 4 mm as the cutoff point. In their study with 58 patients, EMD had been demonstrated to be an important preoperative prognostic factors for RFS in patients with clinical T3 lower rectal cancer (HR: 2.62 95%CI: 1.06–6.65, P = .04). However, the study had limited validation efficiency because of the small sample, only in the lower rectal cancer, and being from a single institute, and insufficient statistical analyses. In addition, all of these studies used the absolute value of EMD, differences of mesorectum between patients with different BMI and different directions of tumor were not considered. However, the mesorectal fat layer is rather thin in Chinese patients, and the mesorectum has been reported to be < 15 mm in the majority of patients in most positions and at most levels. Moreover, the thickness of the mesorectum can vary with the BMI, tumor location, and direction. Besides, the T3a (preoperative staging of ESMO guideline) with depth of invasion <1 mm was difficult to measure on MRI and the distinction of prognosis between T2 stage and T3 stage was not remarkable when the T3 tumor has <1 mm spread. Therefore, the EMD/mesorectum ratio would be a good supplement for the absolute value of EMD. Based on our statistical analyses, the association between EMD/mesorectum ratio ≥ 0.3 and postoperative recurrence and 5-year RFS was remarkable. According to univariate and multivariate analysis, the EMD/mesorectum ratio was the only independent prognostic factor for 5-year RFS. For OS, both MR-LN and resection type were independent prognostic factors. However, regarding resection type (LAR vs APR and Hartmann), we caution against the firm conclusion because of the possibility of selection bias, surgeons would select patients with more-advanced T3 cancer or elder patients to perform APR and Hartmann surgery. Multivariate analysis showed that EMD/mesorectum ratio was not an independent prognostic factor for OS. This could be the result of short follow-up (median 37 months), effective adjuvant chemoradiotherapy and salvage surgery after recurrence. Even so, it's still obvious that EMD/mesorectum ratio ≥ 0.3 is one of the risk factors for postoperative recurrence. So, the optimal cutoff point was theoretically set to a value of 0.3. Then, the EMD/mesorectum ratio was divided into 2 groups: EMD/mesorectum ratio ≥ 0.3 and EMD/mesorectum ratio < 0.3.
Because of the special cone anatomy of the rectum, the mesorectum has different values in different locations and directions. In our study, the mean ratio in the low rectum is 0.48 ± 0.28 and 0.38 ± 0.2 in the middle rectum. The proportion of ratio ≥ 0.3 in the low rectum is 65.0% and significantly higher than the middle rectum (46.5%, P = .002). Besides, tumors located in anterior wall had a higher percentage (75.3%) of having an EMD/mesorectum ratio ≥ 0.3 compared with tumors in the lateral (41.1%) or posterior (56.8%) (P < .001). Moreover, patients with a EMD/mesorectum ratio ≥ 0.3 had a significantly higher proportion of positive MRF compared with patients with an EMD mesorectum ratio < 0.3 (34.4% vs 5.6%, P < .001). Therefore, more attention should be paid to patients with tumor located in anterior wall and lower rectum, further studies could be performed to explore the optimal cut off values in different locations and directions.
Neoadjuvant chemoradiotherapy followed by total mesorectal excision (TME) is currently considered the standard combined modality treatment for patients with LARC.[5–7] Currently, basing on risk stratification, clinicoradiologic prognostic factors are used to identify patients with rectal cancer who would benefit from nCRT. Preoperative MRI assessed MRF involvement is a strong independent predictor of poor outcome in patients with LARC.[23,24] EMVI[17,25,26] and EMD[9–11] detected on MRI are also risk factors for rectal cancer patients. However, studies evaluating the association between EMD detected by MRI and prognosis in patients with rectal cancer are scarce. In our study, patients with EMD/mesorectum ratio ≥ 0.3 had decreased 5-year RFS and OS. Besides, of the 161 patients with EMD/mesorectum ratio ≥ 0.3, the 5-year RFS of patients with nCRT was significantly higher compared with patients without nCRT [86.9% vs 63.2% HR 2.652; 95% CI (1.229–4.357); P = .001]. Therefore, EMD/mesorectum ratio is a reliable imaging marker for T3 subclassification in mid-low rectal cancer and can be used to select high risk patients for nCRT.
There are several limitations in the present study. First, this is a retrospective study with a relatively short follow-up. Second, the study is not a large scale randomized controlled trials and the data from only one center. However, the present data show a strong correlation between the EMD/mesorectum ratio and RFS. Third, the regimens and dose of neoadjuvant therapy were different among the patients with EMD/mesorectum ratio ≥ 0.3, including short course radiotherapy, long course chemoradiotherapy and chemotherapy with different cycles only. Even so, the significant differences of 5-year RFS had demonstrated that patients with EMD/mesorectum ratio ≥ 0.3 could benefit from neoadjuvant therapy.
The EMD/mesorectum ratio was an independent prognostic factor for 5-year RFS of T3 mid-low rectal cancer patients, and the optimal cut off value of EMD/mesorectum ratio was 0.3 when the ratio was applied to classify T3 mid-low rectal cancer patients. nCRT should be performed for these patients when the EMD/mesorectum ratio is ≥ 0.3. However, further prospective study is necessary to prove reproducibility and validity of the cutoff point and the feasibility as an imaging marker of nCRT.
Conceptualization: Chaoyang Gu, Bing Wu, Ziqiang Wang.
Data curation: Chaoyang Gu, Xuyang Yang, Xubing Zhang, Erliang Zheng, Xiangbing Deng, Tao Hu, Qingbin Wu, Liang Bi, Bing Wu, Minggang Su.
Formal analysis: Chaoyang Gu, Xubing Zhang.
Funding acquisition: Ziqiang Wang.
Methodology: Chaoyang Gu, Xuyang Yang, Xiangbing Deng, Bing Wu, Minggang Su, Ziqiang Wang.
Project administration: Chaoyang Gu, Ziqiang Wang.
Software: Xubing Zhang, Liang Bi.
Supervision: Bing Wu, Ziqiang Wang.
Writing – original draft: Chaoyang Gu, Xuyang Yang.
Writing – review & editing: Chaoyang Gu, Ziqiang Wang.
Chaoyang Gu orcid: 0000-0002-4707-4192.
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Keywords:Copyright © 2018 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
extramural distance/mesorectum ratio; magnetic resonance imaging; mid-low rectal cancer; neoadjuvant chemoradiotherapy; prognosis; T3 subclassification