Colorectal cancer liver metastatic disease is a significant clinical problem. 15% to 25% of patients with colorectal cancer present with synchronous liver metastases and up to 85% of these patients have unresectable metastatic liver disease[4, 6]. Hepatic resection combined with chemotherapy is the standard treatment for metastatic rectal cancer patients and can lead to 5-year OS to 40-50%. In our study, the 2-year and 5-year OS in patients with hepatic resection were 87.4% and 48.0%, similar to the findings by other researchers.
Although the only potentially curative treatment for metastatic CRC patients is surgical resection, the majority of the metastatic patients are too advanced to undergo curative surgery. For these patients, whether resection of the primary tumor affords a survival advantage remains a matter of debate. According to the NCCN guidelines, if the primary tumor is not acutely obstructed, palliative resection of the primary is rarely recommended, because incomplete resection (R1/R2 resection) has not been shown to be beneficial. However, two registry studies in the United States suggested that nearly 70% of metastatic CRC patients have undergone resection of the primary site, and both studies observed a significant survival advantage[22, 23]. Matthieu et al reported the outcomes of 810 CRC patients with unresectable synchronous metastases, 59% (n=478) underwent resection of their primary tumor, compared with patients in the non-resection group, the hepatic resection group were more likely to have a lower baseline carcinoembryonic antigen (CEA) and alkaline phosphatase levels, primary tumor resection was independently associated with better OS and progression-free survival (PFS). The median survival of the hepatic resection group and non-hepatic group were 19.2 months and 13.3 months (p<0.001), respectively. Our study suggests a better survival outcome in the unresectable metastases patients who underwent primary site resection. In the metastatic CRC patients, 1387 (24.2%) patients underwent surgery to the primary site (Fig.1).
In the final cohort, 270 (60.3%) metastatic rectal cancer patients did not receive hepatic resection and the median survival in this group was 37.0 months with 2-year, 5-year OS 68.5% and 32.9%. Compare with other studies[24, 25], the overall survival results of the unresectable metastatic rectal cancer patients in this study were satisfactory. After comparing the inclusion criteria of our study to the others, we think the main difference is that we added radiotherapy to our inclusion criteria, and also the constantly updated chemotherapy and radiotherapy play a significant role in the improvement of survival outcomes, especially the application of the total neoadjuvant therapy (TNT) approach in the recent years. The TNT approach, which means induction or consolidation chemotherapy with chemoradiotherapy prior to surgery, was first in the use of the local advanced rectal cancer patients (T3/4, N0, or node-positive). According to a large study conducted by Memorial Sloan Kettering Cancer Center, the complete response (CR) rates in the advanced rectal cancer patients was 36% in the TNT group and 21% in the chemoradiotherapy with planned adjuvant chemotherapy group. They also noted that patients receiving TNT were more likely to complete planned chemotherapy with fewer dose reduction. This was consistent with the idea of intensive systemic therapy for the treatment of unresectable synchronous metastases. Several advantages have also been pointed out by some other relevant studies: improved delivery of planned therapy, increased downstaging, and in-vivo assessment of chemosensitivity[27, 28]. With these advantages, the TNT approach was more likely to convert patients with unresectable synchronous liver metastases into the resectable status.
In our study, we performed univariate and multivariate cox proportional hazard regression analysis for the survival of metastatic rectal cancer patients. Here, we found that non-hepatic resection was the strongest risk factor associated with poor prognosis; this was inconsistent with previous reports[2, 25]. The Cox regression analysis also indicates that male sex was associated with worse prognosis in stage IV patients. Several studies have shown that women are less likely to develop colorectal cancer than men, and women with colorectal cancer have a longer survival time than men[29, 30]. One explanation of the sex differences lies in circulating androgens which will decrease the effectiveness of chemotherapy through the TUBB3 pathway in males. In our study, poorly or undifferentiated tumors account for 14.7% of all malignant neoplasms, but it also shows a significant correlation with poor survival. This might be because poorly or undifferentiated cancer cells display reduced cohesiveness and have a stronger ability to invade surrounding tissues.
One of the greatest strengths of the present study is the large sample size provided by the SEER database, however, as a retrospective database, it has several limitations. First, the seer database lacks some key clinical information that might be important for prognosis, such as tumor markers, margin of resection, comorbidities and complications. Second, the SEER database does not provide detailed information about chemoradiotherapy regimens, biological targeted therapy, which could also influence the prognosis. Third, it is not possible to distinguish patients between those with isolated hepatic metastases or multiple hepatic metastases, and there is little information about the treatment strategies for the liver metastasis, this may affect patients’ prognosis.