The presence of extrahepatic disease (EHD) in patients with CLRM was previously regarded as an absolute contraindication for liver resection [11, 12]. However, with the development of better surgical techniques that allow for complete resection and the emergence of more effective regimens of chemotherapy that shrink both intra- and extrahepatic disease, more patients with EHD are becoming eligible for liver resection [11, 12]. It depends on the possibility of resecting all diseases, including the primary tumor, liver metastases, and EHD [13, 14]. This study revealed that, in CRLM patients with concurrent EHD, resection of liver metastases following systemic chemotherapy is superior to chemotherapy alone, with median OS times of 24 months and 21 months, respectively. Chua et al. clarified that surgery removes the tumor mass, while chemotherapy targets micrometastatic disease . Therefore, combining both modalities would lead to better outcomes. We found that the survival of CRLM patients with EHD who received combined regimens was not influenced by their sex; however, patients with a younger age at diagnosis and white race had a lower 5-year mortality hazard. Meanwhile, a study by Aoki et al. indicated that patient age and sex were insignificant prognostic factors . Surprisingly, Adam et al. reported impressive survival rates of elderly CRLM patients undergoing liver resection and concluded that patients' age should not be regarded as a barrier to surgery .
Our study showed that patients had outcomes that were more favorable when their primary tumors were grade I, located at the rectum, or when they had an EHD located at the lungs. Similarly, a study observed more reduced survival rates following liver resection in patients with liver metastases from right-sided colon cancer . In contrast, Aoki et al. found no significant differences in overall survival between different sites of the primary tumor . Meanwhile, it has been consistently reported in the literature that the location of EHD is an essential prognostic factor [10, 19, 20]. A study found that following complete resection of the EHD, patients with lung metastasis had a better prognosis compared to those with peritoneal or portal and para-aortic nodal metastases. Interestingly, a study by Adam et al. proposed five factors for poor prognosis: right colon cancer, at least 6 liver metastases, EHD location other than lung metastases, EHD concomitant with CLM recurrence, and a carcinoembryonic antigen (CEA) level ≥ 10 ng/mL. The authors observed a higher 5-year survival rate in patients with none of these factors compared to that of patients with three or more factors. Other studies have also addressed further negative prognostic factors, including R1 margin status, largest CRLM greater than 3 cm, portal or retroperitoneal nodal involvement, multiple EHD sites, and high tumor burden in the liver[19, 22–24]. Furthermore, Chua et al identified the Peritoneal Cancer Index (PCI) as a prognostic indicator of survival in CRLM patients with peritoneal carcinomatosis. Lower PCI in these patients made it possible to perform complete cytoreductive surgery for peritoneal disease and thus improved their survival.
To date, the possibility of liver resection to offer a potential cure for patients with EHD is still a debate. Some studies found that disease recurrence is the rule in these patients [19, 26]. For instance, a retrospective review reported a very high rate of disease recurrence following resection, with 90.2% of patients experiencing recurrence at a median of 8 months and 85% of them experiencing systemic recurrence . The patients were rarely cured, and therefore, they considered liver resection in this setting as a non-curative intervention [19, 27]. In contrast, some have postulated that combining targeted molecular therapies with chemotherapy or following a more aggressive approach may offer a potential cure in CRLM patients with concomitant EHD [11, 28]. Such an approach consists of perioperative chemotherapy, resection of all metastatic sites, and re-surgery in case of recurrence [11, 28]. However, even in the absence of curative intent, complete resection is needed to achieve better outcomes. Patients who did not complete two-stage hepatectomy had similar survival rates to patients treated with chemotherapy only . Moreover, the survival of patients undergoing combined resection of CRLM and EHD was better than that of patients undergoing liver resection only or those receiving chemotherapy only [23, 30]. For instance, Hwang et al. indicated that the 5-year overall survival of patients significantly jumped from 0–28% after resecting both hepatic and concurrent EHD .
The current study had several limitations. The data on SEER*Stat only report whether the patient has received chemotherapy or not. Further details of the chemotherapy regimen are not available in SEER, including the given agents and their combinations, the number of cycles, and the sequence of chemotherapy with surgery, preoperative, postoperative, or both. Another limitation is the lack of details about hepatic metastases, including their size and number. Such a shortage in detail has limited our ability to analyze the effect of various chemotherapy protocols and liver disease burden on patient outcomes following liver resection. Moreover, SEER*Stat describes liver resection with resection/ablation without further details on the resection technique.