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INTRODUCTION
Colorectal cancer (CRC) is a common form of cancer, accounting for approximately 13% of newly diagnosed cases [1]. A significant concern is that 15%–25% of CRC cases are diagnosed at stage IV, often accompanied by hepatic metastasis [2]. In the treatment of colorectal cancer liver metastasis (CRLM), a combination of locoregional treatment (such as surgical resection, thermal ablation, and intra-arterial chemotherapy) and systemic therapy is typically employed [34]. Liver transplantation has also been attempted in select patients [5]. However, surgical resection remains a particularly noteworthy option, with reported 5-year and 10-year overall survival (OS) rates of 42% and 25%, respectively [6789].
Several studies have consistently reported CRC sidedness, which has different embryologic origins depending on the primary tumor’s location, resulting in genetic and histopathologic differences and differing prognoses [101112]. Right-sided tumors in CRLM have been reported to have a worse survival rate than left-sided tumors, and liver transplant patients with CRLM have also shown a poor prognosis [1314]. However, there is still debate as to whether sidedness is an independent prognostic factor in CRLM [1415].
The aim of this study was to assess the effect of sidedness on both OS and progression-free survival (PFS) in resectable CRLM and to identify prognostic factors.
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METHODS
Ethics statements
The study protocol conformed to the ethical guidelines of the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of Samsung Medical Center (IRB No. SMC 2024-02-063). The need for informed consent was waived by the IRB due to the retrospective nature of the study.
Patient selection
The study investigated patients who underwent liver resection for CRLM at Samsung Medical Center between January 2008 and December 2022. Exclusion criteria included unresectable CRLM, double primary colon cancer with different primary tumor locations, and R2 resection of liver lesion.
Medical records were reviewed to obtain data on sex, age, presence of synchronous cancer, hepatectomy timing in synchronous cancer, history of chemotherapy, history of concurrent ablation, and CEA levels. Pathology records were also reviewed to gather data on primary site, T stage of primary CRC, N stage of primary CRC, maximum tumor size of hepatic metastasis, and number of tumors. The extent of hepatectomy was determined from operation records and categorized into 2 groups: major and minor. Major liver resections are classified as the removal of more than 3 liver segments, while minor resections involve the removal of 3 or fewer segments. The hepatectomy method and resection status were also investigated based on the operation record, and the hepatectomy method was categorized into anatomical and non-anatomical resection.
Classification of sidedness
Sidedness was categorized into right side and left side based on the distal 2/3 of the transverse colon. For the OS analysis, apart from the right and left division, we also stratified the analysis into 3 groups: right, left, and rectum. The upper rectum was considered separately as rectum, while the rectosigmoid colon was grouped with the left colon.
History of chemotherapy
The history of chemotherapy was examined to determine the presence or absence of chemotherapy and the number of chemotherapy cycles administered before hepatectomy. Chemotherapy was defined as treatment administered after the detection of liver metastasis, and the number of cycles completed prior to surgery was recorded. Patients who did not receive chemotherapy were excluded from the analysis of calculating the distribution of the number of chemotherapy cycles. Neoadjuvant concomitant chemoradiation therapy for rectal cancer was not included in the chemotherapy count.
Classification of recurrence pattern
Recurrence patterns were categorized into local recurrence and distant metastasis. Local recurrence was defined as occurring at the surgical margin of the primary tumor. Patients with local recurrence accompanied by distant metastasis were classified into the distant metastasis group. Distant metastases were further classified into 5 categories: hepatic, pulmonary, peritoneal, distant lymph node, bone, and other. Recurrences were also classified as single- or multiple-organ based on whether a combination of the 5 categories was present.
Statistical analysis
The primary outcome measures were 5-year OS and PFS. For the survival analysis, the Kaplan-Meier estimates and the log-rank test were used. Both the OS and PFS were analyzed using time-to-event regression. The Cox proportional hazard model was used to evaluate prognostic variables, an estimated hazard ratio with a 95% confidence interval (CI) was presented, and P < 0.05 was considered statistically significant. Continuous variables with normal distribution are summarized with mean ± standard deviation, and non-normal continuous variables are expressed as the median (range). The Fisher exact test or Pearson chi-square test was applied to compare proportions between groups as appropriate. For the comparison of continuous variables, the Student t-test or Mann-Whitney U-test was used. All analyses were performed using R software ver. 4.2.1 (The R Foundation).
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RESULTS
Among 499 patients who underwent liver resection for CRLM, 497 were eligible for the inclusion criteria after excluding double primary cancer (n = 2). Across the entire cohort, there were 106 patients on the right-sided group and 391 patients on the left-sided group.
Baseline characteristics
Comparisons of characteristics between the right-sided group and the left-sided group are summarized in Table 1. The right-sided group was older than the left-sided group (right vs. left, 62.6 ± 11.2 years vs. 58.3 ± 11.6 years; P = 0.001) and had a lower prehepatectomy chemotherapy rate (right vs. left, 17% vs. 28.9; P = 0.019). However, there were no differences in sex distribution, concurrent ablation, or CEA. Regarding primary CRC characteristics, there were no differences in the T stage and N stage. In terms of liver metastasis characteristics, the proportion of synchronous metastasis was higher in the right-sided group (right vs. left, 90.6% vs. 80.3%; P = 0.020), but there were no differences in hepatectomy timing in synchronous metastasis, hepatectomy extent, hepatectomy method, resection status, number of tumors, or maximum tumor size of hepatic metastasis.
Survival outcomes according to sidedness
In the survival analysis, the right-sided group exhibited lower 5-year OS (right vs. left, 49.7% vs. 54.2; P = 0.305) and 5-year PFS (right vs. left, 57.1% vs. 60.2%; P = 0.271) compared to the left-sided group, although these differences were not statistically significant. Survival analyses in the 3 groups—right, left, and rectum—also indicated no difference in 5-year OS (right vs. left vs. rectum, 49.7% vs. 53.5% vs. 55.8%; P = 0.512) and 5-year PFS (right vs. left vs. rectum, 57.1% vs. 60.5% vs. 59.7%; P = 0.353) (Fig. 1). In subgroup analysis, there was no difference in 5-year OS (right vs. left, 47.8% vs. 50.4%; P = 0.521) and 5-year PFS (right vs. left, 61.1% vs. 61.9%; P = 0.344) based on sidedness in the synchronous tumor group. For metachronous cancer, 5-year survival analyses were not possible due to insufficient follow-up, thus 3-year survival analyses were conducted. The analysis revealed no difference in 3-year OS (right vs. left, 100% vs. 90.1%; P = 0.468), but PFS showed all recurrences in the right-sided group (P = 0.027) (Fig. 2).
Survival outcomes according to hepatectomy timing
The 5-year OS and 5-year PFS were subjected to further analysis in accordance with the timing of hepatectomy (staged vs. simultaneous) in the context of synchronous tumors. The findings indicated that the staged operation exhibited superior OS (staged vs. simultaneous, 87.5% vs. 49.3%; P = 0.465) and PFS (staged vs. simultaneous, 100% vs. 62.2%; P = 0.276) outcomes, although this difference was not statistically significant (Fig. 3).
Prognostic factor analyses
In the analysis of prognostic factors, synchronous tumor (odds ratio [OR], 5.01; P < 0.001), CEA (OR, 1.46; P = 0.016), and maximum tumor size of hepatic metastasis (OR, 1.09; P = 0.026) were associated with OS in multivariate analysis (Table 2). In the analysis of prognostic factors associated with PFS, synchronous tumor (OR, 0.43; P < 0.001), CEA (OR, 1.48; P = 0.014), and maximum tumor size of hepatic metastasis (OR, 1.06; P = 0.037) were significant in the univariate analysis, but only synchronous tumor (OR, 0.42; P < 0.001) and CEA (OR, 1.40; P = 0.042) remained statistically significant in the multivariate analysis (Table 3).
Recurrence pattern according to sidedness
Comparisons of recurrence pattern between the right-sided group and the left-sided group are summarized in Table 4. There was no difference in the proportion of local recurrence (right vs. left, 4.4% vs. 3.6%; P = 0.678) and distant metastasis (right vs. left, 95.6% vs. 96.4%) based on sidedness, and the types of distant metastasis were similar, with single-organ metastasis accounting for about 70% in both groups (P = 0.981). The proportions of single-organ metastasis (hepatic; right vs. left, 48.4% vs. 36.8%; P = 0.868) also showed no difference in sidedness.
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DISCUSSION
While numerous factors influenced survival in CRC, several studies have reported on the concept of ‘sidedness’, which refers to differences in survival based on the location of the primary tumor [16171819]. Survival outcomes according to sidedness suggest a worse prognosis for right-side colon cancer compared to left-side, and this discrepancy has been attributed to differences in embryonic origin, RAS status, and microsatellite instability [19].
Survival disparities based on the location of the primary tumor have also been observed in CRLM. In unresectable CRLM, right-sided colon cancer is associated with worse survival compared to left-sided colon cancer [20]. However, conflicting results have been reported in resectable CRLM. A meta-analysis of survival after hepatectomy showed that right-sided colon cancer was associated with a poorer prognosis compared to left-sided colon cancer, but Sasaki et al. [14] reported the opposite result. Furthermore, Zhang et al. [15] reported that patients with right-sided colon cancer had worse recurrence-free survival but similar OS.
In our study, we found no differences in OS or PFS based on sidedness. This result is consistent with the findings of Zhang et al. [15], who analyzed 611 patients using propensity score matching (PSM). The main difference between their study and ours is that we did not conduct PSM, and instead performed a subgroup analysis. In the subgroup analysis, synchronous tumors did not show a difference in prognosis based on sidedness. However, in the subgroup analysis of metachronous tumors, OS did not differ by sidedness, but PFS was worse in the right-sided group. Although various factors may have contributed to this outcome, we speculate that the higher proportion of single hepatic metastasis within the metachronous tumor (right vs. left, 30% vs. 67%) on the left side may have played a role.
The right-sided group exhibited a lower proportion of prehepatectomy chemotherapy. In the analysis of subgroups, prehepatectomy chemotherapy did not show any differences in the metachronous group, but the low proportion of prehepatectomy chemotherapy in synchronous tumors had an impact. It appears that this is due to selection bias that arose from our investigation of resectable CRLM rather than the entire CRLM population.
The prognostic factor analysis of our study revealed that resection status did not exert an influence on OS and PFS. Firstly, this result may be attributed to selection bias, whereby patients with a high probability of R2 resection are excluded from the initial selection process for hepatectomy. Furthermore, in the case of R2 resection, all but 3 patients had resections that were not detected and removed due to their small size. Consequently, we consider that the analysis demonstrated that resection status did not affect prognosis.
The postoperative recurrence rate of CRLM is reported to be around 70% [21], and intrahepatic metastasis has been identified as the most common recurrence pattern, although rates vary according to systemic therapy and clinical risk score (CRS) [22]. Recurrence patterns by sidedness also indicate that intrahepatic metastasis is the predominant pattern regardless of the primary tumor location [14]. However, in our study, pulmonary metastasis was identified as the most common single-organ distant metastasis in the left-sided group, although the difference was not statistically significant. Unlike previous studies, we differentiated between single-organ distant metastasis and multi-organ distant metastasis and found that the prevalence of at least one intrahepatic metastasis in multi-organ distant metastasis was more than 80%, regardless of the sidedness.
Various aggressive methods, including consideration of future remnant liver volume, are being explored in the management of CRLM, and liver transplantation is also under investigation [232425]. When considering surgical resection, factors such as size, tumor location, and biological characteristics of the primary tumor should be taken into account to determine resectability [262728]. However, in clinical practice, some patients may present with borderline resectability despite consideration of these factors. If the location of the primary tumor were an independent prognostic factor in these patients, the concept of sidedness could become a critical consideration in clinical decision-making. However, our results confirm that sidedness is not an independent prognostic factor in patients with CRLM.
This study has several limitations, including its retrospective nature and single-center study design. In addition, it did not consider various prognostic factors such as classification of CRS and genomic status (RAS or BRAF status). However, unlike other studies, we exclusively analyzed patients after 2008 onwards and also included patients after 2016, when less invasive liver resections such as laparoscopic liver surgery began to be actively performed [2930].
In conclusion, sidedness was not identified as an independent prognostic factor in resectable CRLM. Instead, prognosis was associated with CEA levels, synchronous tumor, and maximum tumor size of hepatic metastasis. In addition, the patterns of recurrence after hepatectomy did not differ based on sidedness.
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