The liver is the most frequently afflicted metastatic organ second to the lymph nodes for most malignancies (Jaques et al., 1995; Hess et al., 2006; Amankwah et al., 2013; Ryu et al., 2013). The most common tumors with liver metastases arise from the portal venous drainage system, which provides about two-thirds of the liver’s blood supply. Because lesions are usually asymptomatic, liver involvement in metastasis is often neglected and poorly studied, and even extensive infiltration of metastatic tumor may not alter its function or homeostasis until late in the disease (Clark et al., 2016). There are few epidemiological studies on metastatic liver cancer, but 30–70% of patients die of liver metastasis (Pickren J and Lane, 1982) and most patients with liver metastases will die of the primary disease (Gilbert Ha et al., 1982).

As one of the deadliest malignant tumors in the world (Ferlay et al., 2015; Schild and Vokes, 2016), pancreatic cancer is the eighth most common cause of cancer in males and the sixth most common cause of cancer in females. In decades, a large number of studies have shown that the development of pancreatic cancer was closely related to age. The aging trend of the population in the world is challenging the current treatments and caring for patients with pancreatic cancer (Bray et al., 2018; Ferlay et al., 2018). The underlying mechanisms of pancreatic cancer is complicated and uncertain, accompanied with poor prognosis (Maisonneuve, 2019). According to the original site in pancreas, pancreatic cancer is classified as endocrine and exocrine pancreatic cancer, and the latter is more common and has a higher risk of mortality in both females and males (Fesinmeyer et al., 2005). Additionally, the majority of exocrine pancreatic cancer is adenocarcinoma (Li, 2001; Cowgill and Muscarella, 2003). Approximately 50% of pancreatic cancer patients are diagnosed with distant metastases (Mayo et al., 2012), and the most common site of distal metastases found at autopsy was the liver, followed by the peritoneum, lungs and pleura, bones, and adrenal glands (Kamisawa et al., 1995; Mao et al., 1995; Embuscado et al., 2005; Disibio and French, 2008). Previous studies suggested risk factors of pancreatic cancer involving smoking, positive family history and genetics, diabetes, obesity, dietary factors, alcohol consumption, and physical inactivity (Yadav and Lowenfels, 2013; Ilic and Ilic, 2016). Age, race, tumor size, grade, lymph node metastasis (Mayo et al., 2012), AJCC stage (Kamarajah et al., 2017) and treatment (Ansari et al., 2019) are also reported associated with the survival of pancreatic cancer patients. However, evidence for prognostic factors in pancreatic cancer with distant metastasis is rare. However, evidence for prognostic factors in pancreatic cancer with distant metastasis is rare. Moreover, Andrew A et al. and previous studies reported that treatment strategies for pancreatic cancer differentiate in diverse range of ages (Wheeler and Nicholl, 2014). Thus, the objective of this study is to determine the differences in primary sites of metastatic liver cancer between males and females. Furthermore, we evaluated the prognostic risk factors of pancreatic cancer metastasis to liver at different ages of diagnosis through the Cox regression model.

It was reported that 90% cancer-related deaths resulted from metastasis of the primary tumor. The formation of local infiltrates and metastases are clinically most relevant to the progression of cancer (Christofori, 2006). Organ damage due to growth-related lesions, paraneoplastic syndromes, or treatment complications was significantly associated with morbidity and mortality of metastatic disease (Steeg, 2006). In general, cancer metastasis can be divided into different stages from local invasion, intravasation, survival in circulation, extravasation, finally to colonization and metastasis (Hanahan and Weinberg, 2011). The unique biological characteristics of the liver make it a vulnerable site for tumor metastasis: 1) structural and hemodynamic features - characteristic microcirculation in the liver makes it easier for diffuse tumor cells carried in the blood to enter. In addition, molecules on the surface of hepatic nonparenchymal cells (NPCs) lining the hepatic capillaries contribute to the adhesion and retention of circulating tumor cells. The pore on the hepatic sinusoidal endothelial cell (LSECs) facilitates the tumor cells to enter the basement membrane directly; 2) regenerative capabilities—the cellular tissue remodeling mechanism involved in self-renewal and reconstruction that promotes intratumoral stroma and blood vessel formation through signals generated by tumor cells, creating an enabling environment for survival and growth; 3) regional immunosuppression—the general foreign body reaction is reduced to limit potential damage to the liver, resulting in a relatively tolerant microenvironment that allows for the survival and growth of foreign tumor cells (Vidal-Vanaclocha, 2011; Clark et al., 2016).

Pancreatic cancer is the fourth leading cause of cancer-related death worldwide, and its main metastatic site is liver (Stott et al., 2010). Studies have shown that, in addition to smoking, a family history of pancreatic cancer, black race, diabetes, and increased body mass index were also predictors of pancreatic cancer mortality (Coughlin et al., 2000). A lack of early signs and symptoms, as well as high aggressiveness, leads to a low survival rate. The prognosis of patients with pancreatic cancer is closely related to tumor stage and tumor grade/aggressiveness (Bolm et al., 2015) that can only be evaluated by biopsy or surgery. Our present data showed tumor grade was also a significant predictor of overall survival and cancer-specific survival in patients with liver metastasis, independent of age at diagnosis (Table 3, Table 4). In addition, 85% of the histology types of pancreatic cancer are ductal adenocarcinoma of the pancreas (PDAC) (Ryan et al., 2014; Hogendorf et al., 2018). For patients with PDAC, younger age, male sex, larger tumor size, low ALT level and high CA 19-9 level could predict unexpected distant metastasis (Liu et al., 2018). Histologically, pancreatic adenocarcinoma accounts for the largest proportion in pancreatic cancer (Simard et al., 2012), accompanied with the worst prognosis, and the most common site of metastasis is liver (Lemke et al., 2013; Deeb et al., 2015; Kumar et al., 2015), which is consistent with our results (Table 2). Our data suggested that most histologic types of pancreatic metastases to liver were adenocarcinomas. The prognosis of patients with pancreatic cancer with liver metastasis was poorer than that of patients with distant lymph node metastasis or lung metastasis. The factors predicting the better prognosis included age<65 years, white race, being married, female sex and surgery treatment (Oweira et al., 2017). Furthermore, our study showed that the younger the age, the higher the overall survival rate of patients with pancreatic cancer with liver metastasis (Figure 4). In addition, we found differences in prognostic factors among the groups after grouping by age at diagnosis. Histologically, compared with pancreatic adenocarcinoma, ductal and lobular neoplasms and epithelial neoplasms were associated with poor overall survival in the group age >52 years old, while the latter were not correlated with the prognosis in group age <52 years old. In the multivariate regression analysis, histological type was a significant predictor for cancer-specific survival only for patients diagnosed at age >52 years old. AJCC N1 stage with significance in predicting poor overall survival only in group age 52–69 years old, and predicting poor cancer-specific survival only in group age <52 years old. (Table 3, Table 4).

At present, the only treatment for pancreatic cancer is surgery, and adjuvant therapy based on chemotherapy can improve the survival rate (McGuigan et al., 2018). For elderly patients (age>80 years old), postoperative adjuvant chemotherapy is critical to the prognosis (Sho et al., 2016). Surgery is limited to patients with localized disease, and metastatic spread is often considered a contraindication to resection, regardless of whether it is observed synchronously or ectopic (Seufferlein et al., 2012). However, metastatic excision or local treatment is occasionally performed in centers around the world based on individual clinical experience, and there is no objective evidence to guide treatment methods taking into account patient choice or metastatic spread (Gleisner et al., 2007; Shrikhande et al., 2007; De Jong et al., 2010; Nentwich et al., 2012; Edwards et al., 2013). In general, palliative chemotherapy with FOLFIRONOX (mFOLFIRINOX with 5-fluorouracil) is the preferred chemotherapy regimen for metastatic pancreatic cancer (McGuigan et al., 2018). Despite this, T. Hackert (Hackert et al., 2017) proved that resection of liver or interaortocaval lymph nodes (ILN) metastases could be superior to palliative treatment for pancreatic cancer patients with metastasis. Mitsuka et al. (2020) found that the median survival time was significantly improved for patients diagnosed between 44 and 83 years old who underwent liver resection or pancreatectomy. Other study (Warschkow et al., 2020) showed that lymphadenectomy had only 18% direct effect on improved overall survival, while 82% of its effect were mediated by other factors like treatment at high-volume hospitals and adjuvant chemotherapy for patients whose median age were 66 years. However, the analysis on differences among different ages of patients is scarce. As we know, there is insufficient evidence that the efficacy of different therapies in patients with metastatic pancreatic cancer is age-related. Our data showed chemotherapy alone was the most important prognostic factor for patients who diagnosed at younger age, and age of diagnosis was the most prognostic factor for patients diagnosed at an older age. For the diagnosis of pancreatic cancer at all ages, surgery was the best treatment method to improve the overall survival rate of patients with pancreatic cancer with liver metastasis (Table 3). Considering the tumor-specific survival rate, surgery combined with chemotherapy is the best choice for patients under 69 years of age at the time of diagnosis, while surgery alone is the best choice for patients aged 69–84 years at the time of diagnosis. In addition, surgery alone and combined chemotherapy were significantly superior to chemotherapy alone in terms of overall survival and tumor-specific survival (Table 3, Table 4). Interestingly, in a case report (Katsura et al., 2019), after the combination therapy of pancreatoduodenectomy and chemotherapy, a 66-year-old patient with pancreatic ductal carcinoma metastasis to liver showed the disappearance of liver metastasis and without other new metastasis. This case report partially confirms the conclusion from our analysis that surgery alone was the optimal treatment in group age>69 years old, while surgery combined with chemotherapy was the best option in the other groups. Both surgical treatment and chemotherapy cause damage to human bodies. Especially, the elderly can hardly bear the double blow, as surgical treatment and chemotherapy both exerting in therapy. In addition, chemotherapy is often accompanied with many side effects. The analyzed data in this manuscript demonstrates that surgical treatment alone is superior to surgery plus chemotherapy in patients older than 69 years of age. It suggests that surgery should be a priority for the older population (age>69) with pancreatic cancer metastasis to liver. Certainly, clinical treatment selection depends on the multiple assessment of patient, and this manuscript provides an epidemiological reference for the selection of clinical treatment.

Although the SEER database provides a large amount of clinical data, there are still many limitations in our research. First, we need to further conduct a follow-up clinical trial to verify this result. Second, we did not include patients undergoing radiotherapy because of the small number of cases, and we need to compare the effects of radiotherapy, chemotherapy and surgery on prognosis. Finally, the sequence of chemotherapy and surgery, the diverse methods of surgery and chemotherapy can be further studied.

In this population-based analysis, we found the main primary sites of metastatic liver cancer are lung and brunchu, sigmoid colon and pancreas. Furthermore, we explored the prognostic factors of pancreatic cancer metastasis to liver grouped by age at diagnosis. Tumor grade, histology and treatment are valid prognostic factors in all age groups. Additionally, gender and AJCC N stage in age<52 years old, while race and AJCC N stage in age>69 years old were predictors. Surgery alone was the optimal treatment in group age>69 years old, whereas surgery combined with chemotherapy was the best option in the other groups. In conclusion, these findings would help to choose better treatment for patients with metastatic liver cancer.