Prognostic risk factors for pT4 colon cancer: A retrospective cohort study
- Authors:
- Published online on: November 28, 2022 https://doi.org/10.3892/ol.2022.13615
- Article Number: 29
Abstract
Introduction
Colorectal cancer is the fourth most common cancer, with 1.8 million cases worldwide as of 2017. It is also the second most common cause of cancer-related mortality, accounting for 896,000 deaths globally in 2017 (1). The depth of tumor invasion, which is classified into T status, is one of the poor prognostic factors, and T4 disease accounts for approximately 15% of all primary colon cancer (2,3). In the 7th edition of AJCC TNM classification in 2010, pathological T4 (pT4) was divided as tumor invasion through the visceral peritoneum (T4a) and to the adjacent organs or structures (T4b) (4) because a large study using National Cancer Data Base showed that pathological T4a (pT4a) had better 5-year survival rate than pathological T4b (pT4b) (5,6).
This classification is still applied today; however, there is no difference in the prognosis between pT4a and pT4b (7,8). A noteworthy point may be differences in the recurrence pattern between pT4a and pT4b colon cancer. The ratios of peritoneal recurrence were higher in pT4 colon cancer than in the other pT status colon cancer, ranging from 18.3 to 42.1% in previous studies (7–10). pT4a colon cancer had more frequent peritoneal recurrence than pT4b colon cancer (8). Conversely, R1 resection leads to some recurrence (especially locoregional recurrence) in pT4b colon cancer requiring multivisceral en block resection (MVR), and surgical technique also plays a role in prognosis (11). R1 resection is a poor prognostic factor for locally advanced colon cancer requiring MVR (12).
Poor prognostic factors for pT4 colon cancer remain incompletely elucidated. Understanding the oncological characteristics of pT4 colon cancer, including the tumor-specific differences between pT4a and pT4b colon cancer, can assist surgeons in providing the best possible treatment. Therefore, we investigated the prognostic risk factors for pT4 colon cancer in patients who underwent R0 resection. Toward this goal, we compared oncological outcomes, including overall survival (OS), relapse-free survival (RFS), and recurrence pattern, between patients with pT4 vs. pT4b colon cancer. Additionally, the independent risk factors for pT4 colon cancer were examined.
Materials and methods
Patient selection criteria
Overall, 1,066 patients underwent surgery for primary colorectal cancer between 2014 and 2021 at Tokyo Women's Medical Hospital. Among these cases, 83 patients who underwent curative resection excluding emergency surgery and were diagnosed with pT4 colon cancer were enrolled. The patients with stage II–III cancer with lesions located between the cecum and rectosigmoid colon were included, but patients with stage IV colon cancer or R1 resection were excluded. En bloc MVR with complete mesocolic excision to achieve R0 resection was performed for patients with locally advanced colon cancer if tumors were invading or adhering to multiple organs or structures. The surgical approach included open, laparoscopic, and robotic surgery, and the most appropriate method was selected based on patient and tumor factors. A robotic approach was first used at our institution in 2017. The anastomosis in the minimally invasive surgery was not performed using the intra-corporeal functional end-to-end anastomosis technique. Conversion from the minimally invasive approach to an open approach was assigned to the open group. We collected medical data using the electronic medical records of these patients and analyzed them retrospectively. This study was approved by the Ethics Committee of Tokyo Women's Medical Hospital (Institutional Review Board number 5266).
Patient evaluation and perioperative treatment
Patient characteristics (age, sex, and body mass index [BMI]) were collected from the medical database. All patients were diagnosed with adenocarcinoma via biopsy and underwent colonoscopy and multidetector-row computed tomography (CT) or positron emission tomography (PET-CT) pre-operatively. Tumor status (tumor size, histology, pathological T stage and pathological N stage) and details concerning the surgical approach were obtained from the medical database. Pathological stage was determined according to the 8th edition of the TNM classification of malignant tumors (13). Regarding tumor location, the right colon was defined as the cecum and transverse colon, and the left colon was defined as the descending colon and the rectosigmoid colon.
Postoperative follow-up
Postoperative adjuvant chemotherapy was recommended for all patients based on their individual health status. Routine follow-up was performed every 3 months by consultation and included blood tests for tumor markers. Either CT or PET-CT was performed every 6 months. Additional examinations were performed in cases of suspected recurrence.
Statistical analysis
The baseline demographic information and long-term oncological outcomes (follow-up duration and recurrence site) were described and compared between the pT4a and T4b groups. Categorical data are presented as numbers and proportions and were compared between the two patient groups using Fisher's exact test. Continuous numerical variables are presented as median and interquartile range (IQR). The Mann-Whitney U test was used to compare the distribution of continuous numerical variables between the pT4a and pT4b groups. Patient characteristics (age, sex, BMI), tumor (tumor size, histology, tumor location, pT status, and pN status), and treatment-related variables (surgical approach, adjuvant chemotherapy) were used as potential risk factors for postoperative peritoneal recurrence, as described in previous studies (7,8). Factors of interest identified at the univariate level (P<0.10) were entered into a multivariate Cox regression model. The effects of these putative factors on recurrence risks are described as the hazard ratio (HR) and corresponding 95% confidence intervals (CIs). Statistical significance was set at a two-sided P-value of <0.05. Kaplan-Meier estimates were used to examine OS and RFS curves. The log-rank test was performed to compare long-term outcomes between the pT4a and pT4b groups. Among the patients with recurrence, OS with and without peritoneal recurrence, and with and without distant metastasis alone were also analyzed similarly. All statistical analyses were performed using SPSS version 24 (SPSS Inc., Chicago, IL, USA).
Results
Baseline demographics of patients
The baseline patient demographics, tumor characteristics, and treatment-related factors of the sample are summarized in Table I. There were no significant differences in patient characteristics, including age, sex, and BMI, between the pT4a group (n=62) and the pT4b group (n=21). Tumor size was, however, significantly larger in the pT4b group than in the pT4a group (P=0.033). The difference in the tumor location between the two groups was 37 cases (59.5%) (cecum: 6, ascending colon: 16, transverse colon: 15) vs. 8 cases (38.1%) (cecum: 2, ascending colon: 6) for the right-sided colon and 25 cases (40.3%) (descending colon: 4, sigmoid colon: 14, rectosigmoid colon: 7) vs. 13 cases (61.9%) (sigmoid colon: 11, rectosigmoid colon: 2) for the left-sided colon (P=0.128). The proportions of MVR were 4.8 and 100% in the pT4a and pT4b groups, respectively. The adjacent organs or structures resected for en bloc complete tumor resection were the peritoneum or abdominal wall (n=13), bladder (n=5), small intestine (n=4), other parts of the colon (n=3), duodenum (n=2), liver (n=1), ovary (n=1), gonadal vessels (n=1), omentum (n=1), and pararenal fat (n=1). Of these, it is in the pT4a group that there were the peritoneum or abdominal wall (n=3), omentum (n=1), and pararenal fat (n=1). Conversion from laparoscopy to open surgery was observed in one case. There were no significant differences in the surgical approach or use of postoperative adjuvant chemotherapy between the pT4a and pT4b groups.
Oncological outcomes including recurrence pattern
The oncological outcomes are summarized in Table II. The median (IQR) follow-up duration was comparable between the two groups (38.5 [15.8-55.0] months vs. 34 [14.5-58.5] months, P=0.917). Disease recurrence was observed in 17 (27.4%) and 8 (38.1%) patients in the pT4a and pT4b groups, respectively (P=0.413). Furthermore, peritoneal recurrence tended to occur more frequently in the pT4a group than in the pT4b group (19.4 vs. 9.5%, P=0.501), while distant metastasis ratio tended to be higher in the pT4b group than the pT4a group (11.3 vs. 28.6%, P=0.082). Five (71.4%) of the seven patients in the pT4b group who experienced recurrence were distant metastasis alone. The 3-year OS rates were 85.1% in the pT4a group and 95.0% in the pT4b group, respectively (P=0.089) (Fig. 1). The 3-year RFS rates were 64.1% in the pT4a group and 60.5% in the pT4b group, respectively (P=0.589) (Fig. 1). The 3-year peritoneal recurrence-free survival rate tended to be lower in the pT4a group than in the pT4b group (71.0 vs. 90.2%, P=0.085) (Fig. 2).
Risk factors for overall and recurrence-free survival
Table III presents the independent risk factors associated with OS and RFS. In univariate and multivariable analyses, OS was associated with mucinous or poorly differentiated adenocarcinoma (HR, 6.828; 95% CI, 2.173-21.456; P=0.001), right-sided colon cancer (HR, 4.290; 95% CI, 1.119-16.446; P=0.034), and pN status positive (HR, 5.060; 95% CI, 1.387-18.462; P=0.014). Conversely, poor prognostic factors were histologically confirmed mucinous or poorly differentiated adenocarcinoma (HR, 3.114; 95% CI, 1.375-7.052; P=0.006) and pN status positive (HR, 7.845; 95% CI, 2.706-22.745; P<0.001).
 | Table III.Risk factors for overall survival and relapse-free survival in patients with pT4 colon cancer. |
Discussion
This study investigated prognostic risk factors for pT4 colon cancer when radical resection was performed, including a comparison between the pT4a and pT4b groups. There were no statistical differences in OS and RFS between the pT4a and pT4b groups; however, there was a trend toward more disseminated recurrence in the pT4a group. Histology (mucinous or poorly differentiated adenocarcinoma) and pN status (positive) were associated with OS and RFS, and tumor location (right-sided) was an independent risk factor for OS in patients with pT4 colon cancer.
Before 2010, several studies had shown that tumor invasion through the visceral peritoneum is associated with a worse prognosis than invasion to the adjacent organs or structures (14–16). Subsequently, in the 7th edition of AJCC TNM classification (2010), pT4 was divided into pT4a and T4b4, since a large study using National Cancer Data Base showed pT4a had a better 5-year survival rate than pT4b (5). However, recent studies showed no difference between pT4a and pT4b, which is similar to our results (7,8). In our study, pT groups were not significantly associated with survival. Tumor location, histology, and pN status were associated with OS, and histology and pN status were risk factors for RFS. These findings are consistent with those of previous studies, which suggested that tumor location (right-sided), histology (mucinous or poor differentiated adenocarcinoma) and pN status were associated with a poorer prognosis (5,12,17,18), especially right-sided colon cancers characterized by mucinous histology, high microsatellite instability, and BRAF mutation carrier status (17,18).
Although pT4a colon cancer is expected to be more likely to cause peritoneal recurrence than pT4b colon cancer, studies have often failed to prove this with statistical significance. Our study also demonstrated a tendency for the pT4a group to be more prone to recurrence of peritoneal recurrence than the pT4b group (19.4 vs. 4.8%, P=0.168). At least one prior study showed this effect could be due to a type II statistical error, and demonstrated that the pT4a group had more peritoneal recurrence than the pT4b group in the absence of this error (8). Interestingly, in our study, the pT4b group showed a trend toward more distant as opposed to peritoneal recurrence (11.3 vs. 28.6%, P=0.082). Peritoneal recurrence was associated with a poorer prognosis than was no peritoneal recurrence (P=0.009). However. the prognosis was poor in the presence of peritoneal recurrence, while distant metastasis alone was associated with a better prognosis than other recurrence patterns (P=0.039) (Fig. 2). Therefore, strategies that consider the recurrence pattern of pT4a vs. pT4b colon cancer are required for oncologists. A previous review of three large phase III randomized trials suggested that developing peritoneal recurrence led to poorer OS than other forms of recurrence (19).
A randomized controlled trial comparing open and laparoscopic surgery for colon cancer (JCOG0404) also found no significant differences in the rate of peritoneal recurrence between the two approaches (20). Conversely, a conflicting study showed an association between the laparoscopic approach and increased risk for peritoneal recurrence (21). We believe that it is important to avoid direct contact with the tumor as much as possible during laparoscopic surgery for pT4a, since the cancer cells are exposed on the surface of the serosa and may be disseminated by the surgical procedure. Conversely, it must be recommended that R0 resection with MVR is always required for patients in the pT4b group. The surgical approach should be selected according to the surgical-skill level of the institution and that of the surgeon to prevent R1 resection by the surgical procedure, as proposed in our previous study (12).
This study has some limitations. First, this was a retrospective study with a small sample size that included surgical data from a single institution. Second, this study had a selection bias for patients in terms of the surgical approach. However, this decision was based on the capacities of the research institution, which is in keeping with real-world clinical practice. Third, only a few patients received postoperative adjuvant chemotherapy. In contrast, the major strength of this study is its focus on patients with colon cancer who underwent R0 resection without primary involvement of the rectum. This is because locally advanced colon cancer is more prone to peritoneal recurrence than rectal cancer, and the treatment including surgical difficulty, is standardized. Finally, large-scale studies with multicenter designs would be required to generalize our findings.
In conclusion, our findings suggest that patients with pT4b colon cancer and R0 resection may not have a poorer prognosis compared to those with pT4a colon cancer. However, the possibility that patients with pT4a colon cancer had more peritoneal recurrence than those with pT4b colon cancer may have affected the survival rates. Histology (mucinous or poorly differentiated adenocarcinoma) and pN status (positive) were significant prognostic factors for OS and RFS, and tumor location (right-sided) was also associated with OS.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
The study concept and design were developed by TK and SY. Data collection was performed by TK, RN, YN, FM, KT, HK, KK, YK, YB, SO, YI and MI. The analysis was performed by TK. The manuscript was prepared by TK. The manuscript was supervised by SY. All authors reviewed the manuscript. TK and RN confirm the authenticity of all the raw data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
This study was approved by the Ethics Committee of Tokyo Women's Medical Hospital (Institutional Review Board number 5266). The committee waived the requirement for informed consent.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Authors' information
Dr Tsutomu Kumamoto, ORCID: 0000-0002-7177-9328.
Glossary
Abbreviations
Abbreviations:
|
pT4 |
pathological T4 |
|
OS |
overall survival |
|
RFS |
relapse-free survival |
|
MVR |
multivisceral en bloc resection |
|
BMI |
body mass index |
|
CT |
computed tomography |
|
PET |
positron emission tomography |
|
IQR |
interquartile range |
|
HR |
hazard ratio |
|
CI |
confidence interval |
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