Research ArticleClinical Studies
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Positive Circumferential Resection Margin in Rectal Cancer Is a Robust Predictor of Poor Long-term Prognosis With Clinicopathological Bias Between Groups Compensated by Propensity-score Matching Analysis

KIICHI SUGIMOTO, HIROMITSU TAKAHASHI, YUKI, TAKAHIRO IRIE, MEGUMI KAWAGUCHI, AYA KOBARI, KOTA AMEMIYA, YUKI TSUCHIYA, SHUNSUKE MOTEGI, RYOICHI TSUKAMOTO, KUMPEI HONJO, YU OKAZAWA, MASAYA KAWAI, SHUN ISHIYAMA, MAKOTO TAKAHASHI, ROBERT M. HOFFMAN and KAZUHIRO SAKAMOTO
Anticancer Research August 2023, 43 (8) 3623-3630; DOI: https://doi.org/10.21873/anticanres.16542

Abstract

Background/Aim: Circumferential resection margin (CRM) is the most reliable predictor of local and distant recurrence in locally-advanced rectal cancer (LARC). The present study was conducted to compare the long-term outcomes between CRM (+) and (−) groups using propensity-score (PS) matching analysis to compensate for bias between groups. Patients and Methods: Of 563 consecutive patients with Stage II/III rectal cancer who were treated surgically with curative-intent at Juntendo University Hospital between Jan 1989 and Mar 2018, 412 patients were enrolled retrospectively in the study. The patients were divided into a CRM (+) group (n=21; 5.1%) and a CRM (−) group (n=391; 94.9%). Results: In the entire cohort, recurrence-free survival (RFS), local recurrence-free survival (LRFS), non-local recurrence-free survival (NLRFS), and cancer-specific survival (CSS) were significantly worse among patients in the CRM (+) group compared with those in the CRM (−) group. Univariate analysis demonstrated patients in the CRM (+) group had significantly larger primary tumors (p=0.02), more frequently had open surgery (p=0.009), had an abdominoperineal resection (APR) procedure (p=0.01) and a T4 primary tumor (p<0.0001). After PS matching analysis, in the propensity-matched cohort, RFS, LRFS, NLRFS and CSS were significantly worse among patients in the CRM (+) group compared with those in the CRM (−) group. Conclusion: PS matching analysis demonstrated that RFS, LRFS, NLRFS, and CSS were significantly worse among patients in the CRM (+) group compared with those in the CRM (−) group. The present results indicate that CRM (+) is a robust predictor of long-term outcome of LARC, independent of tumor size.

Key Words:

Colorectal cancer is a leading global cause of death and an increasingly common disease worldwide (1, 2). Rectal cancer accounts for approximately 30% of colorectal cancers (1). Rectal cancer often demonstrates an aggressive phenotype with poor long-term outcomes, including recurrence-free and cancer-specific survival (3). Preoperative strategies have improved postoperative outcomes for locally-advanced rectal cancer (LARC) (4, 5). In cases of resectable LARC, neoadjuvant chemoradiotherapy (NACRT), followed by total mesorectum excision (TME), is now thought to be the best strategy in Western countries (3, 6, 7). However, preoperative treatment for LARC is not a mainstay in Japan (8-10). Despite such strategies, LARC still has a local-recurrence rate of 5-10%, even after curative-intent resection (11-15). The distant metastasis rate of 25-40% is the main cause of treatment failure in patients with LARC (16, 17). A wide variety of perioperative biomarkers such as those determined by imaging [extramural venous invasion (EMVI), mesorectal fascia involvement, etc.], blood markers [CEA, neutrophil lymphocyte ratio (NLR), etc.], and pathological markers [tumor grade, tumor infiltrating lymphocytes (TIL), etc.] are used as prognostic factors for LARC (18-20). Circumferential resection margin (CRM) is the most reliable predictor of local and distant recurrence in LARC (18). Patients with a positive CRM are more likely to demonstrate poor long-term outcomes, compared with those with a negative CRM. However, the larger the tumor, the higher the risk of a positive CRM (21). Therefore, there have been some differences in characteristics, such as maximum diameter of the primary tumor, invasion depth, tumor differentiation, between the CRM-positive and-negative groups in previous analyses (21, 22).

The present study was conducted to compare the long-term outcomes between the CRM-positive and-negative groups using propensity score (PS) matching analysis in order to have more accurate prognostic data by compensating for bias between the two groups.

Patients and Methods

Patient selection. The scheme of the present study is shown in Figure 1. Of 563 consecutive patients with Stage II/III rectal cancer who were treated surgically with curative-intent at Juntendo University Hospital between Jan 1989 and Mar 2018, 40 patients with neoadjuvant treatment [neoadjuvant chemoradiotherapy (NACRT) or neoadjuvant chemotherapy (NAC)], 26 patients with tumors pathologically invading to adjacent organs (pT4b), 13 patients with synchronous colorectal cancer, three patients with recurrence of cancer of other organs, and 69 patients with incomplete data, were excluded from this study. Finally, 412 patients were enrolled retrospectively in the study. The patients were divided into a CRM (+) group (n=21; 5.1%) and a CRM (−) group (n=391; 94.9%). Data were collected in a retrospective review of a database and medical records. CRM (+) was defined as a tumor identified at the radial margin of the resection plane (23). Briefly, pathological examination of the resected specimen was as follows (24, 25): fresh specimens received immediately after resection were opened along the antimesenteric border and washed with tap water. After fixation for 48 hours with 10% buffered formalin, a longitudinal slice approximately 3 mm thick was made through the point of maximum penetration of the tumor. Several parallel slices were occasionally needed to determine whether CRM was positive or negative. The study was conducted in accordance with the Declaration of Helsinki. The study was approved by the institutional review board (IRB) of Juntendo University Hospital (No. 19-214). The requirement for written informed consent was waived because of the study’s retrospective design.

Figure 1.
Figure 1.

Study schema. Of 563 consecutive patients with Stage II/III rectal cancer who were treated surgically with curative-intent at Juntendo University Hospital between Jan 1989 and Mar 2018, 412 patients were enrolled retrospectively in the study. The patients were divided into a circumferential resection margin (CRM) (+) group (n=21; 5.1%) and a CRM (−) group (n=391; 94.9%). Finally, 21 patients in the CRM (+) group and 42 patients in the CRM (−) group were matched in 1:2 pair PS matching analysis.

Surgical strategies for rectal cancer. Rectal cancer was resected with lymph node dissection at the root of the main vessels (inferior mesenteric arteries and veins) with curative-intent (23). The standard treatment of rectal cancer is radical TME surgery (25). For LARC operations, the dissection line was set at least 2 cm distal to the cancer. Sphincter preservation is possible if there is a 2-cm mucosal margin above the dentate line (26). Otherwise, abdominoperineal resection (APR) was performed. Open or laparoscopic surgery was indicated based on tumor-related factors (tumor site and extent of cancer progression) and patient-related factors (obesity, history of abdominal surgery). We note that these indications changed to some extent over the period of the study.

Postoperative adjuvant chemotherapy. The regimen was selected based on age and clinicopathological factors. The regimen for each case was finally decided based on a discussion between the physician and patient. Adjuvant chemotherapy was started 4 to 8 weeks postoperatively. Patients with neoadjuvant treatment were excluded from the study because CRM may become ambiguous due to neoadjuvant treatment.

Clinicopathological analysis. Clinicopathological factors [age, sex, location in the upper rectum (above the peritoneal reflection) or the lower rectum (below the peritoneal reflection)], surgical approach (open/laparoscopic), surgical procedure (APR/others), main macroscopic type (localized/diffuse) (23), maximum diameter of primary tumor, predominant histological type of primary tumor (differentiated/undifferentiated), undifferentiated component in primary tumor (present/absent), T classification (T1-3/T4) (27), N classification (N0/N1, 2) (27), and survival were analyzed in the present study.

Follow-up. Postoperative follow-up procedures included clinical assessment and serum CEA measurements every 3 months, chest computed tomography (CT) and abdominal ultrasonography or CT every 3-6 months. If necessary, abdominal or pelvic magnetic resonance imaging (MRI) or positron emission tomography (PET)-CT was used to detect a recurrent lesion. Local recurrence was defined as local extraperitoneal tumor recurrence, tumor growth in local lymph nodes, intraluminal tumor recurrence or peritoneal tumor growth below the promontory (28). Distant metastases were defined as tumor recurrence in an organ outside the pelvis such as lungs, liver, lymph nodes, peritoneum and/or any other distant organ (28).

Propensity score matching analysis. Differences in clinicopathological severity between the CRM (+) and (−) groups were adjusted by PS matching analysis. The PS was estimated, and the log odds of the probability of a patient with positive CRM [CRM (+) group] was modeled with potential confounders of patient background factors and tumor characteristics with p<0.05 in univariate analyses between the CRM (+) and (−) groups. The C-statistic was calculated to determine the propensity model discrimination. 1:2 pair PS matching analysis with calipers <0.05 was performed.

Statistical analysis. Recurrence-free survival (RFS: time from initial surgery for rectal cancer until first recurrence of the disease), local recurrence-free survival (LRFS: time from initial surgery for rectal cancer until local recurrence of the disease), non-local recurrence-free survival (NLRFS: time from initial surgery for rectal cancer until recurrence other than local recurrence, i.e., hematogenous metastasis or cancerous peritonitis) and cancer-specific survival (CSS: time from surgery until cancer-related death) were determined with the Kaplan–Meier method, and significance was evaluated by univariate analyses using a log-rank test. Discrete and continuous variables were compared with the Fisher exact test and Mann–Whitney U-test, respectively. JMP 14 (SAS Institute Inc., Cary, NC, USA) was used for all analyses, with differences considered significant at p<0.05. Values are shown as median (minimum - maximum).

Results

RFS, LRFS, and CSS in the whole cohort. The median observation period was 67.4 months (range=8.3-204.5 months) for recurrence-free surviving patients. RFS was significantly worse among patients in the CRM (+) group (5-year RFS: 15.7%) compared with those in the CRM (−) group (5-year RFS: 70.2%) (HR=4.26, 95%CI=2.54-7.14, p<0.0001) (Figure 2A). In addition, LRFS was significantly worse among patients in the CRM (+) group (5-year LRFS: 49.3%) compared with those in the CRM (−) group (5-year LRFS: 92.6%) (HR=7.04, 95%CI=3.18-15.59, p<0.0001) (Figure 2B). NLRFS was significantly worse among patients in the CRM (+) group (5-year NLRFS: 31.5%) compared with those in the CRM (−) group (5-year NLRFS: 73.6%) (HR=3.48, 95%CI=1.94-6.24, p<0.0001) (Figure 2C). CSS was also significantly worse among patients in the CRM (+) group (5-year CSS: 26.5%) compared with those in the CRM (−) group (5-year CSS: 86.3%) (HR=6.97, 95%CI=3.70-13.13, p<0.0001) (Figure 2D).

Figure 2.
Figure 2.

Recurrence-free survival (RFS), local recurrence-free survival (LRFS), non-local recurrence-free survival (NLRFS), and cancer-specific survival (CSS) of the entire cohort. RFS was significantly worse among patients in the CRM (+) group (5-year RFS: 15.7%) compared with those in the CRM (−) group (5-year RFS: 70.2%) (HR=4.26, 95%CI=2.54-7.14, p<0.0001) (A). In addition, LRFS was significantly worse among patients in the CRM (+) group (5-year LRFS: 49.3%) compared with the CRM (−) group (5-year LRFS: 92.6%) (HR=7.04, 95%CI=3.18-15.59, p<0.0001) (B). NLRFS was significantly worse among patients in the CRM (+) group (5-year NLRFS: 31.5%) compared with those in the CRM (−) group (5-year NLRFS: 73.6%) (HR=3.48, 95%CI=1.94-6.24, p<0.0001) (C). CSS was also significantly worse among patients in the CRM (+) group (5-year CSS: 26.5%) compared with those in the CRM (−) group (5-year CSS: 86.3%) (HR=6.97, 95%CI=3.70-13.13, p<0.0001) (D).

Clinicopathological factors in the CRM (+) and (−) groups. Univariate analysis indicated that surgical approach (open/laparoscopic), surgical procedure (APR/others), maximum diameter of primary tumor and T classification (T1-3/T4) differed significantly between the CRM (+) and (−) groups. Patients in the CRM (+) group had a significantly larger primary tumor (p=0.02); more frequently had open surgery (p=0.009); more frequent APR procedures (p=0.01); and had a T4 primary tumor (p<0.0001) (Table I). There were no significant differences in other clinicopathological factors between the two groups.

View this table:
Table I.

Clinicopathological factors in the circumferential resection margin (CRM) (+) and (−) groups before and after propensity score matching.

PS was estimated with potential bias of surgical approach, surgical procedure, age, maximum diameter of primary tumor and T classification. The median PS was 0.193 (0.005-0.360) in the CRM (+) group and 0.009 (0.005-0.356) in the CRM (−) group (p<0.0001). Since the area under the ROC curve (AUROC) is equivalent to model discrimination, the C-statistic of 0.858 (95%CI=0.760-0.955, p<0.0001) showed satisfactory discrimination (Figure 3). Twenty-one patients in the CRM (+) group and 42 patients in the CRM (−) group were matched in 1:2 pair PS matching analysis (Figure 1). There were no significant differences in univariate analysis of clinicopathological factors between the CRM (+) and (−) groups after PS matching (Table I).

Figure 3.
Figure 3.

Receiver operating characteristic (ROC) curve and C-statistic. Since the area under the ROC curve (AUROC) is equivalent to model discrimination, the C-statistic of 0.858 (95%CI=0.760-0.955, p<0.0001) showed satisfactory discrimination.

RFS, LRFS, and CSS in the propensity-score-matched cohort. RFS was significantly worse in the propensity-score-matched cohort among patients in the CRM (+) group (5-year RFS: 15.7%) compared with those in the CRM (−) group (5-year RFS: 57.9%) (HR=2.72, 95%CI=1.38-5.37, p=0.004) (Figure 4A). In addition, LRFS was significantly worse among patients in the CRM (+) group (5-year LRFS: 49.3%) compared with those in the CRM (−) group (5-year LRFS: 84.2%) (HR=3.58, 95%CI=1.23-10.44, p=0.02) (Figure 4B). NLRFS was significantly worse among patients in the CRM (+) group (5-year NLRFS: 31.5%) compared with those in the CRM (−) group (5-year NLRFS: 65.5%) (HR=2.33, 95%CI=1.09-4.99, p=0.03) (Figure 4C). CSS was also significantly worse among patients in the CRM (+) group (5-year CSS: 35.3%) compared with those in the CRM (−) group (5-year CSS: 71.3%) (HR=3.52, 95%CI=1.56-7.93, p=0.002) (Figure 4D).

Figure 4.
Figure 4.

Recurrence-free survival (RFS), local recurrence-free survival (LRFS), non-local recurrence-free survival (NLRFS), and cancer-specific survival (CSS) in circumferential resection margin (CRM) (+) and (−) patients in the propensity-score-matched cohort. RFS was significantly worse in the propensity-matched cohort among patients in the CRM (+) group (5-year RFS: 15.7%) compared with those in the CRM (−) group (5-year RFS: 57.9%) (HR=2.72, 95%CI=1.38-5.37, p=0.004) (A). In addition, LRFS was significantly worse among patients in the CRM (+) group (5-year LRFS: 49.3%) compared with those in the CRM (−) group (5-year LRFS: 84.2%) (HR=3.58, 95%CI=1.23-10.44, p=0.02) (B). NLRFS was significantly worse among patients in the CRM (+) group (5-year NLRFS: 31.5%) compared with those in the CRM (−) group (5-year NLRFS: 65.5%) (HR=2.33, 95%CI=1.09-4.99, p=0.03) (C). CSS was also significantly worse among patients in the CRM (+) group (5-year CSS: 35.3%) compared with those in the CRM (−) group (5-year CSS: 71.3%) (HR=3.52, 95%CI=1.56-7.93, p=0.002) (D).

Discussion

CRM for rectal cancer has been analyzed since 1986 (29). CRM has been established to predict risk of local recurrence (29-34). There is still a debate about an adequate definition of CRM for increased recurrence risk. Some studies reported a CRM of 2 mm was a more adequate predictor for recurrence than a CRM of 1 mm (31, 32). However, most studies demonstrated that a decreased CRM distance increased the risk of local recurrence or distant metastases and shorter survival time (28, 30, 33). Particularly, a CRM of 0 mm, which is CRM (+) in our definition, demonstrated a higher risk of local recurrence (30, 33) and distant metastases (28, 30). The proportion of CRM of 0 mm ranged from 1.8% (153/8,593) (31) to 8.0% (129/1,613) (21), which is equivalent to the present study (5.0%). When a CRM of 0 mm was defined as CRM (+), risk factors were tumor perforation or tumor adherence to other organs or high-grade tumors (21). This indicates that larger tumors are more likely to invade the surface of the resected plane, which can lead to local recurrence. Therefore, the biases relating to tumor-related factors need to be balanced to investigate the clinical significance of CRM in LARC. In the present study, the maximum diameter of the primary tumor and T classification (T1-3/T4) differed significantly between the CRM (+) and (−) groups resulting in more open surgery and APR in the CRM (+) group. Therefore, the clinical impact of CRM was examined using PS matching analysis to compensate for this potential bias. There is increasing use of the PS matching method to counter the effects of confounding factors in observational studies of the effects of treatment on outcome (35). Baseline data in the whole cohort indicated CRM (+) was associated with more severe tumor aggressiveness in terms of the tumor size, but 1:2 pair PS matching balanced these factors between the CRM (+) and (−) groups. We believe the present study is the first use of PS matching analysis to examine the clinical impact of CRM (+) on LARC. The present results indicate that CRM (+) is a robust predictor for RFS, LRFS, NLRFS, and CSS irrespective of the tumor size after PS matching.

CRM has also been reported to be a powerful predictor of distant metastases (28-30). In the present study, a significant difference in terms of non-local recurrences (NLRFS) between the CRM (+) and (−) groups was also observed after PS matching. Previous studies have demonstrated that patients with CRM (+) are more likely to develop distant metastases. A nation-wide population-based study demonstrated that patients with a CRM ≤1.0 mm had a higher risk of distant metastases compared with those with a CRM >1.0 mm (28). The development of distant metastases in LARC was reported to originate from a complex process comprising anatomical, morphological, molecular, and genetic factors (36). Especially, increased risk of distant metastases is related to factors including tumor deposits (TD) and EMVI in LARC (37). Therefore, we estimated that CRM (+) can lead to these factors, which may increase the risk of distant metastases. Since there were no data regarding TD and EMVI in the present study, further investigation is needed with these factors to obtain conclusive results.

There are some limitations to the present study. First, data were collected only for a small number of patients from a single institution. Second, the proportion of the patients who underwent NACRT, which was a gold standard for cure in LARC, was small, although those patients were excluded from the present study because the indications for preoperative treatment changed to some extent over the period of the present study. Third, the CRM distance was not evaluated with circular specimens. There are different methods to measure CRM by focusing on the distance from the intestinal wall to the surface of the tumor (29). The measurement of CRM with circular specimens is useful for exact CRM evaluation (38-40). In the PRODUCT trial (40), the semi-opened circular specimen-processing method enabled detailed examination for pathological findings. This processing method could detect the margin positivity in 26 out of 303 patients (8.6%) (CRM ≤1 mm), including positive CRM at the site other than the main tumor i.e., at metastasized lymph nodes in six patients (2.0%), at a tumor nodule in one patient (0.3%) or at intra-lymphatic duct invasion in one patient (0.3%). However, long-term results were not analyzed in this study (40).

Conclusion

The present study used PS matching analysis to compensate for bias in pathological factors of rectal cancer patients undergoing surgery in order to determine the prognostic differences of patients whose tumor had a positive or negative CRM. The results of the present study show a significantly poorer prognosis of patients with a positive CRM. Therefore, great care must be taken during surgery to eliminate a positive margin wherever possible.

Footnotes

  • Authors’ Contributions

    Sugimoto K developed the concept of the study and drafted the article. Sugimoto K, YI, TI, Kawaguchi M, AK, KA, YT, SM, RT, KH, YO, Kawai M, SI, MT, and Sakamoto K recruited patients. Sugimoto K and Sakamoto K obtained IRB approval for the protocol of the study. The article was revised by RMH and has been approved by all Authors.

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest in relation to this study.

  • Received May 3, 2023.
  • Revision received May 21, 2023.
  • Accepted May 22, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Positive Circumferential Resection Margin in Rectal Cancer Is a Robust Predictor of Poor Long-term Prognosis With Clinicopathological Bias Between Groups Compensated by Propensity-score Matching Analysis
KIICHI SUGIMOTO, HIROMITSU TAKAHASHI, YUKI, TAKAHIRO IRIE, MEGUMI KAWAGUCHI, AYA KOBARI, KOTA AMEMIYA, YUKI TSUCHIYA, SHUNSUKE MOTEGI, RYOICHI TSUKAMOTO, KUMPEI HONJO, YU OKAZAWA, MASAYA KAWAI, SHUN ISHIYAMA, MAKOTO TAKAHASHI, ROBERT M. HOFFMAN, KAZUHIRO SAKAMOTO
Anticancer Research Aug 2023, 43 (8) 3623-3630; DOI: 10.21873/anticanres.16542
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