Tsai TJ, Syu KJ, Huang XY, Liu YS, Chen CW, Wu YH, Lin CM, Chang YY. Identifying timing and risk factors for early recurrence of resectable rectal cancer: A single center retrospective study. World J Gastrointest Surg 2024; 16(9): 2842-2852 [PMID: 39351564 DOI: 10.4240/wjgs.v16.i9.2842]
Corresponding Author of This Article
Yu-Yao Chang, Doctor, Division of Colon and Rectal Surgery, Department of Surgery, Changhua Christian Hospital, No. 135 Nanxiao Street, Changhua 50006, Taiwan. 177176@cch.org.tw
Research Domain of This Article
Surgery
Article-Type of This Article
Retrospective Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Author contributions: Tsai TJ wrote the manuscript; Syu KJ, Huang XY and Liu YS collected the data; Chang YY guided the study; Chen CW, Wu YH and Lin CM provided the study design and data analysis. All authors reviewed, edited, and approved the final manuscript and revised it critically for important intellectual content, gave final approval of the version to be published, and agreed to be accountable for all aspects of the work.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Changhua Christian Hospital.
Informed consent statement: All study participants, or their legal guardian, provided informed written consent prior to study enrollment.
Conflict-of-interest statement: The authors declare no conflict of interest.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yu-Yao Chang, Doctor, Division of Colon and Rectal Surgery, Department of Surgery, Changhua Christian Hospital, No. 135 Nanxiao Street, Changhua 50006, Taiwan. 177176@cch.org.tw
Received: March 20, 2024 Revised: July 18, 2024 Accepted: July 26, 2024 Published online: September 27, 2024 Processing time: 181 Days and 19.4 Hours
Abstract
BACKGROUND
Colorectal cancer is a common malignancy and various methods have been introduced to decrease the possibility of recurrence. Early recurrence (ER) is related to worse prognosis. To date, few observational studies have reported on the analysis of rectal cancer. Hence, we reported on the timing and risk factors for the ER of resectable rectal cancer at our institute.
AIM
To analyze a cohort of patients with local and/or distant recurrence following the radical resection of the primary tumor.
METHODS
Data were retrospectively collected from the institutional database from March 2011 to January 2021. Clinicopathological data at diagnosis, perioperative and postoperative data, and first recurrence were collected and analyzed. ER was defined via receiver operating characteristic curve. Prognostic factors were evaluated using the Kaplan–Meier method and Cox proportional hazards modeling.
RESULTS
We included 131 patients. The optimal cut off value of recurrence-free survival (RFS) to differentiate between ER (n = 55, 41.9%) and late recurrence (LR) (n = 76, 58.1%) was 8 mo. The median post-recurrence survival (PRS) of ER and LR was 1.4 mo and 2.9 mo, respectively (P = 0.008) but PRS was not strongly associated with RFS (R² = 0.04). Risk factors included age ≥ 70 years [hazard ratio (HR) = 1.752, P = 0.047], preoperative concurrent chemoradiotherapy (HR = 3.683, P < 0.001), colostomy creation (HR = 2.221, P = 0.036), and length of stay > 9 d (HR = 0.441, P = 0.006).
CONCLUSION
RFS of 8 mo was the optimal cut-off value. Although ER was not associated with PRS, it was still related to prognosis; thus, intense surveillance is recommended.
Core tip: Definitions of early recurrence (ER) in resectable rectal cancer are scare, and the guidelines for surveillance of postoperative condition differ. This study provides information on the ER cutoff time and emphasizes the importance of the intense surveillance of postoperative patients, especially during the first year after surgery. Our study also provides the risk factors for early recurrence.
Citation: Tsai TJ, Syu KJ, Huang XY, Liu YS, Chen CW, Wu YH, Lin CM, Chang YY. Identifying timing and risk factors for early recurrence of resectable rectal cancer: A single center retrospective study. World J Gastrointest Surg 2024; 16(9): 2842-2852
Colorectal cancer is third most common malignancy and second leading cause of cancer-related mortality[1]. In the USA, colorectal cancer is one of most common cancers regardless of gender, accounting for an estimated 8%–9% of deaths[2]. Although multimodal treatment has evolved to reduce the recurrence rate, it continues to increase with higher stage.
Local recurrence occurs more frequently in locally advanced rectal cancer. In the 20th century, the rate decreased from 50% to 20%–30% in patients who received abdominoperineal resection[3]. Preoperative concurrent chemoradiotherapy (CCRT), total mesorectal excision and radial margin identification were introduced to decrease the local recurrence rate to 4%–8%[4-6].
Postoperative surveillance and adjuvant therapy are used to reduce the recurrence rate. Approximately 80% of recurrences manifest with the initial 3 years after surgery and 95% within 5 years[7,8]. For rectal cancer, the 5-year cumulative incidence of recurrence is 9.5% for stage 1, 18.4% for stage 2, and 28.8% for stage 3[9].
Early recurrence (ER) is related to worse prognosis, including of pancreatic cancer[10], gastric cancer[11], liver cancer[12], and lung cancer[13]. To date, few observational studies have reported analysis of ER in local advanced rectal cancer[14] or resected nonmetastatic rectal cancer[15]. Therefore, we reported on timing and risk factors for the ER of resectable rectal cancer at our institute.
MATERIALS AND METHODS
Study population
This retrospective study was performed at the Changhua Christian Hospital between March 2011 and January 2021. It was approved by the local Ethics Commission (submission ID: 220619). All clinical data of participants were collected from electronic medical record system of Changhua Christian Hospital. The patient data included clinical findings, treatment history, imaging results, histological results, and follow-up data.
Aims and criteria
The aim of the study was to analyze a cohort of patients with local and/or distant recurrence following radical resection of primary tumor. The primary endpoints were recurrence-free survival (RFS), post-recurrence survival (PRS) and overall survival (OS). The secondary endpoints were to assess demographic, clinicopathological and treatment characteristics and to identify possible risk factors for ER. The inclusion criteria were: (1) Rectal cancer confirmed via postoperative histology; (2) Receiving radical resection; and (3) Negative resection margins. The exclusion criteria were: (1) Unresectable rectal cancer; (2) History of familial adenomatous polyposis, ulcerative colitis or Crohn’s disease; (3) Postoperative death within 3 mo; (4) Local excision; and (5) Age < 18 years.
Definition
The tumor stages were determined according to the tumor–node–metastasis system (TNM) of American Joint Committee on Cancer. Preoperative carcinoembryonic antigen (CEA) measurements were made prior to surgery. An elevated CEA was defined as > 5 ng/mL. The tumor location was defined as the distance above the anal verge, as observed via colonoscopy. Neoadjuvant chemoradiotherapy was performed for locally advanced rectal cancer before surgery. Emergency surgery was performed in cases of bowel obstruction that did not resolve with medical or endoscopic intervention, or in cases of uncontrolled bleeding and perforation.
Recurrence
The first instance of recurrence was analyzed. Recurrent disease was classified as local, distant, or multiple metastases. Local recurrence was defined as the regrowth of the tumor within the pelvic cavity. Distant recurrence was defined as any recurrence outside the pelvic cavity. Multiple recurrence was defined as recurrence beyond two sites. Distant sites of recurrence were further stratified into liver metastases, pulmonary metastases, lymph node or peritoneum. Lymph node recurrence included all lymph node enlargement except that in the mesentery and peritoneum, diagnosed comprehensively using ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography-CT (PET-CT), and physical findings. OS was defined as the time from surgery to either death or final follow-up. RFS was calculated from the date of surgery to the date of recurrence or last follow-up if recurrence did not occur. PRS referred to the time from first relapse to either death or last follow-up.
Follow-up
The patients were followed up after surgery. After hospital discharge, the patients were followed-up regularly every 3 mo during the first 3 years, every 6 mo from years 4 to 5, and once a year afterward. Most routine follow-up observations included physical examination, laboratory tests, abdominal ultrasonography or CT, colonoscopy and PET-CT to confirm or exclude potential recurrence. Whole body bone scans were performed for those with highly suspicious bone metastases.
Statistical analysis
Receiver operating characteristic (ROC) curves were calculated initially with the intention to divide the two groups of patients with respect to long-term prognosis. We observed which period of time had the highest Youden index (sensitivity + specificity 1) to predict long-term outcome rates and used it as an indicator to separate the groups into early and late recurrence (LR). Potential risk factors for early rectal recurrence were assessed using the Kaplan–Meier method. Cox’s proportional hazard model was used to assess risk factors for RFS. Variables that showed an association with RFS (P < 0.2) and ER in Kaplan–Meier curves were included as covariates in a multivariate Cox proportional hazards model. The results were displayed as hazard ratio (HR) with corresponding 95% confidence interval (CI). Statistical analyzes were performed using SPSS® software, version 25. All graphs were prepared with GraphPad Prism 9 software (GraphPad Software, Inc., Boston, MA, USA) and Excel.
RESULTS
Clinicopathological characteristics of the patients
The study collected 131 patients with recurrence after radical resection for rectal cancer between March 2011 and January 2021 at the Changhua Christian Hospital. The demographic, perioperative clinicopathological, and treatment characteristics are summarized in Table 1. The median follow-up was 41.4 mo (range: 3.4–135.6 mo). The median RFS was 10.8 mo (95%CI: 13.0–17.7 mo). The patients most often experienced distal recurrence (n = 71, 54.2%), followed by local recurrence (n = 30, 22.9%), and multiple recurrence (n = 30, 22.9%). In terms of distal recurrence, the liver and lungs were the most common sites. The median OS in the study was 41.2 mo (95%CI: 42.7–54.1 mo) with 37 patients (28.2%) currently alive. The median PRS was 2.0 mo (95%CI: 2.4–3.2 mo). The probability density plot of survival revealed the recurrent cases peaked at 15 mo and PRS occurred at 2.7 mo (Figure 1). The OS peaked at 48.2 mo after surgery. The coefficient of determination (R²) revealed the strength of associations between RFS and OS (R² = 0.307), but not between RFS and PRS (R² = 0.04) (Figure 2).
Figure 2 Correlation between all patients.
A: Recurrence-free survival (RFS) and overall survival; B: RFS and post-recurrence survival.
Table 1 Clinicopathological characteristics of all patients, n (%).
Variable
Total (n = 131)
Age, year
65 (14)
BMI, median (IQR)
24.09 (21.06-26.82)
Gender, male
82 (62.6)
Tumor diameter, cm
4.3 (2.2)
Tumor location
Upper
29 (22.1)
Middle
46 (35.1)
Low
56 (42.7)
Preoperative CEA, median (IQR)
5.1 (2.3-12.5)
Preoperative Hb, median (IQR)
12.5 (11.00-13.7)
Preoperative CCRT
28 (21.4)
Emergency operation
2 (1.5)
Laparoscopic method
89 (67.9)
Cover to open
3 (2.3)
Blood loss, mL, median (IQR)
50 (30-100)
Colostomy
91 (69.5)
Operation time, median (IQR)
228 (165-295)
Postoperative ICU
3 (2.3)
Pathological T
1
3 (2.3)
2
23 (17.6)
3
94 (71.8)
4
11 (8.4)
Pathological N
0
46 (35.1)
1
46 (35.1)
2
39 (29.8)
Pathological stage
1
17 (13)
2
29 (22.1)
3
85 (64.9)
LNR, %, median (IQR)
5.9 (0-21.1)
Histology
Adenocarcinoma
125 (95.4)
Mucinous adenocarcinoma
6 (4.6)
Histological differentiation
Well
2 (1.5)
Moderate
122 (93.1)
Poor
7 (5.3)
Vascular invasion
20 (15.3)
Lymphatic invasion
115 (87.8)
Perineural invasion
63 (48.1)
RAS gene mutation
71 (54.2)
Complications
46 (35.1)
Clavien–Dindo
0
85 (64.9)
1
9 (6.9)
2
19 (14.5)
3
18 (13.7)
Intraabdominal abscess
6 (4.6)
Ileus
18 (13.7)
SSI
12 (9.2)
Anastomosis leakage
16 (12.2)
Reoperation
18 (13.7)
Readmission
13 (9.9)
LOS, d, median (IQR)
9 (7-12)
Median of survival (mo, IQR)
Recurrence-free survival
10.8 (5.3-22.5)
Post-recurrence survival
2.0 (0.9-4.1)
Overall survival
41.2 (22.1-69.1)
Death
94 (71.8)
Local recurrence
30 (22.9)
Distant recurrence
71 (54.2)
Multiple recurrence
30 (22.9)
Liver
43 (32.8)
Lung
40 (30.5)
Lymph node
22 (16.8)
Peritoneum
9 (6.9)
Defining ER and LR
We classified 131 patients into ER and LR groups by constructing a ROC curve between RFS and death to estimate the optimal threshold, then assessed the impact of ER on OS using Kaplan–Meier analysis. The optimal cutoff value was determined to be the point of the ROC curve closest to the upper-left corner of the graph. The cutoff RFS was 8 mo. Thus, we defined patients whose RFS was < 8 mo as ER patients. Table 2 shows a comparison of the clinicopathological features of the ER and LR groups.
Patients with ER tended to have worse histological differentiation and higher readmission rates. Patients with LR received preoperative CCRT more often. Patients with ER (n = 55, 42.0%) had a median RFS of 4.9 mo (95%CI: 4.3–5.3 mo), with a median PRS of 1.4 mo (95%CI: 1.6–2.7 mo), whereas the median RFS in the LR (≥ 8 mo) (n = 76, 57.9%) was 20.2 mo (95%CI: 20–25.9 mo) followed by a median PRS of 2.9 mo (95%CI: 2.7–3.8 mo). The median OS was significantly longer for patients with LR (62.5 mo, 95%CI: 54–68.5 mo) than for patients with ER (22.9 mo, 95%CI: 24–37.2 mo, P < 0.001) (Figure 3A). Likewise, the median PRS of patients with LR (2.9 mo, 95%CI: 2.7–3.8 mo) was significantly longer (P = 0.008) than that of patients with ER (1.4 mo, 95%CI: 1.6–2.7 mo) (Figure 3B).
Figure 3 Kaplan–Meier curves.
A: Overall survival between early and late recurrence (LR); B: Post-recurrence survival between early and LR.
Independent risk factors associated with RFS of ER
We examined potential risk factors of ER in patients who developed recurrence after operation, and corresponding Kaplan–Meier curves for RFS were generated based on different variables with a primary endpoint of ER (RFS < 8 mo) The Kaplan–Meier curves revealed that length of stay > 9 d, preoperative CCRT, histological differentiation, stoma creation, lymphatic invasion and age > 70 years were each potentially associated with RFS recurrence within 8 mo after surgery (P < 0.2). A further multivariate Cox regression analysis revealed four variables as independent predictive indicators for ER of resectable rectal cancer patients developing recurrence after surgery, including age ≥ 70 years (HR = 1.752, P = 0.047), preoperative CCRT (HR = 3.683, P < 0.001), colostomy creation (HR = 2.221, P = 0.036), and length of stay > 9 d (HR = 0.441, P = 0.006) (Supplementary Figures 1 and 2).
DISCUSSION
ER is generally associated with worse survival outcome in multiple cancers, leading to both shorter RFS and reduced quality of life. However, despite there being numerous previous reports on ER, there remains no exact definition of ER in rectal cancer. Tsai et al[16] and Huh et al[17] set the timescale at 1 year after surgery, Ryuk et al[18] and Aghili et al[19] set it at 2 years, Lan et al[20] at 3 years and Oh et al[21] at 5 years for pT1 patients undergoing transanal local excision. All of these previous researchers set the interval arbitrarily, without objective evaluation. Recently, a minimum P-value approach was used to decide the cutoff value of RFS to divide the patients into ER and LR groups based on OS. Zheng et al[14] described the ER of locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy as being 2 years, while Yan et al[22] set it at 26 mo. Although ER has been studied in specific pattern of rectal cancer, the definition of a cutoff time for resectable rectal cancer without transanal excision is lacking. Different from past researches, we used a ROC curve method to select the cutoff value and we identified a correlation between RFS with OS and between RFS with PRS. Although OS was influenced, PRS was not. These findings were similar to those of Affi Koprowski et al[15], who posited that ER is not associated with PRS. In cased where prolonged RFS influenced OS, PRS was able to estimated survival more objectively. Patients with ER who experience local recurrence and distant metastasis had worse outcomes. Our study revealed that patients with ER had a tendency for lower local recurrence, although it was not significant (ER vs LR 29% vs 43%, P = 0.094).
ER leads to shorter RFS and may be associated with poor tumor biology or disease severity, followed by more rapid progression to death. Although local recurrence in patients with rectal cancer is higher[20], neoadjuvant chemoradiotherapy treatment can reduce it, especially in locally advanced rectal cancer[23]. The most common metastatic site was the lungs, followed by the liver. Our results revealed that the single metastasis rates for the lungs and liver were similar and were the most common sites of metastasis. Therefore, performing chest and abdominal CT or MRI is necessary during patient follow-up after rectal cancer treatment.
Several factors were associated with ER after rectal cancer surgery, including elevated preoperative CEA, higher TNM staging, positive circumferential resection margin, perineural invasion, poor differentiation, positive lymph nodes, and lymphovascular invasion[14,22]. Elevated preoperative CEA is often associated with worse tumor biology, and it is an effective indicator for predicting the clinical outcome of rectal cancer surgery[24,25]. Disease stage is one of most important factors for recurrence and disease-free survival, and is associated with postoperative adjuvant chemotherapy. Positive circumferential resection margin is related to local recurrence, metastasis and OS[26,27]. Perineural invasion and lymphovascular invasion were acknowledged as prognostic factors in a previous study[16] and, in our study, were consistent with less preoperative chemoradiotherapy and poorer differentiation.
For patients with resectable rectal cancer, complete surgical removal offers a higher likelihood of cure and better prognosis. In addition, acceptable postoperative morbidity and mortality must also be considered. Our study revealed preoperative, perioperative and postoperative clinical and pathological characteristics. A Cox proportional hazards model was used to present prognostic factors for ER, including age > 70 years, preoperative chemoradiotherapy, colostomy creation and length of hospital stay > 9 d. For older patients, postoperative morbidity was more frequent and led to a longer length of stay. Longer length of stay led to fewer complications related to surgery and readmission. Therefore, our study revealed that longer length of stay has a low HR. Preoperative chemoradiotherapy was used in cases of locally advanced rectal cancer, which meant a higher recurrence rate. Colostomy creation was performed in patients with lower rectal cancer or preoperative CCRT. For these cases, anastomotic leakage is associated with high local recurrence and poor survival[28]. Symptomatic anastomotic leakage also caused severe adverse events. For patients receiving a defunctioning stoma, a short-term survival benefit was present due to the mitigation of clinical consequences. However, the long-term mortality and oncological outcomes did not differ between patients with a defunctioning stoma and those without[29]. One possible explanation for the high HR associated with colostomy creation may be related to the lower rectal cancer, although the influence of the distance of tumor from the anal verge on the oncological outcome is disputed[30].
Although ~70% of colorectal cancer is curative, recurrence occurred in ~23% of cases, including local relapse and distant metastasis recently. The curative resection of distant metastasis affects the OS, emphasizing the important of intensive surveillance. Most recurrences occurred within 2.2 years and all occurred with 5 years[31]. Published guidelines recommend different protocols, primarily for stage 2 and 3 disease, including taking a medical history and conducting physical examination, measuring CEA levels, carrying out abdominal, pelvic and chest imaging, and conducting endoscopy[32]. More intensive approaches are controversial. Our results revealed that 8 mo should be the cutoff value for ER. Thorough and intense surveillance may facilitate clinicians in making therapeutic decisions to improve patients’ chance of survival and enhance their quality of life.
There are some limitations worthy of statement. First, this was a retrospective study involving a single center with a small sample size. Second, treatments can differ in the post-recurrence phase as target therapy may be added.
CONCLUSION
Patients undergoing resection for rectal cancer who are aged > 70 years, receiving preoperative CCRT and/or have a length of stay > 9 d are most at risk of ER within 8 mo. ER is associated with OS but not PRS and should not be considered an independent factor of survival without metastatic disease. Intense surveillance is recommended in order to identify ER, in addition to direct efforts towards finding treatment options for local and oligometastatic recurrences.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: Taiwan
Peer-review report’s classification
Scientific Quality: Grade B, Grade C, Grade C
Novelty: Grade B, Grade B, Grade C
Creativity or Innovation: Grade B, Grade B, Grade C
Scientific Significance: Grade B, Grade B, Grade B
P-Reviewer: Farouk S; Wang TJ; Yu YB S-Editor: Qu XL L-Editor: Kerr C P-Editor: Zhang L
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