In this study, we examined the effect of neoadjuvant chemotherapy combined with arterial chemoembolization on short-term clinical outcomes of LAGC. Our data showed that compared with conventional group, combined group did not increase adverse events of chemotherapy and postoperative complications. In contrast, the operation time and postoperative hospital stay in the combined group were shorter than those in the conventional group. Furthermore, this study demonstrated that pre-treatment NLR, pre-treatment PLR and arterial chemoembolization were significant predictors of pCR after neoadjuvant therapy.
Arterial chemoembolization is widely used in the treatment of advanced hepatocellular carcinoma. [31–33] It was rarely reported that the arterial chemoembolization was applied in LAGC. Nakajima et al. revealed that arterial chemotherapy of cisplatin and etoposide on days 6 and 20 after intravenous chemotherapy with fluorouracil and calcium folinate in patients with unresectable gastric cancer significantly improved tumor response and resection rates. [34] Zhang et al. compared the effect of different administration methods on patients with unresectable gastric cancer. Patients were divided into two groups: one group received chemotherapy with XELOX regimen, and the other group received chemotherapy with FLEEOX regimen (after 5 days of continuous intravenous infusion of fluorouracil and calcium folinate, the oxaliplatin, epirubicin, and etoposide were injected intra-arterially on days 6 and 20, respectively.). The study found that FLEEOX regimen greatly improved R0 resection rate, median OS and DFS, but had no significant impact on chemotherapy toxicity and postoperative complications. [35] A retrospective study involving 128 patients with unresectable advanced gastric cancer showed that compared with systemic chemotherapy, systemic chemotherapy combined regional arterial chemoembolization did not increase chemotherapy adverse events. In addition, combined therapy also effectively improved the OS, DFS and clinical response rate. [18] Similarly, in our study, combined group did not increase chemotherapy adverse events and postoperative complications in patients with LAGC. The patients in the combined group had a higher pCR rate than those in the conventional group.
Several studies have shown that patients with LAGC who achieve pCR after neoadjuvant therapy have better oncological outcomes. [36–38] However, the influencing factors of pCR in LAGC still remain unclear. Becker et al. suggested that pCR was related to tumor location, degree of differentiation, chemotherapy regimen and times of chemotherapy. [39] In this study, the pCR rate in the combined group was significantly higher than that in the conventional group. Arterial chemoembolization enhanced the anticancer effect by increasing the concentration of chemotherapeutic drug in tumor area and prolonging the drug reaction time. [40] Embolization of tumor trophoblastic vessels reduced tumor blood supply, which resulted in necrosis of tumor cells. Moreover, arterial chemotherapy could inhibit tumor cell proliferation by inducing tumor cell apoptosis, thereby improving the efficacy of neoadjuvant therapy. [41]
Inflammation, considered as an important factor affecting the occurrence and progression of tumors, contributes to tumor growth, invasion, metastasis, angiogenesis, and chemoresistance. [42–43] Several studies have found that pre-treatment NLR is an independent effect factor for pCR of breast cancer patients. [44–46] Lore et al. also found that patients with locally advanced rectal cancer with pre-treatment NLR > 4.06 had poor tumor response and DFS to chemoradiotherapy. [47] In addition, Shi et al. also showed that pre-treatment NLR was an independent predictor of pCR after neoadjuvant chemoradiotherapy for locally advanced rectal cancer. [26] As with colorectal and breast cancers, studies have indicated that pre-treatment NLR, PLR and LMR (lymphocyte to monocyte ratio) were the predictors for tumor regression response and oncological outcomes in LAGC patients after neoadjuvant therapy. [48–51] Unexpectedly, multivariate analysis also revealed that pre-treatment NLR and pre-treatment PLR were independent predictors of pCR after neoadjuvant therapy in this study. It has been shown that neutrophils were capable of secreting chemokines, cytokines and matrix-degrading proteases. Cytokines stimulated tumor microangiogenesis, and matrix-degrading proteases increased tumor adhesion and promoted distant metastasis. [52–53] Platelets were able to promote epithelial mesenchymal transformation and metastatic tumor progression through cytokines (e.g., VEGR, EGF, platelet-derived growth factor, hepatocyte growth factor, TGF-β.). [54–56] Lymphocytes may inhibit tumor cell proliferation and migration by inducing cytotoxic cell death. In addition to this, lymphocytes played a crucial role in the immune surveillance, recognition and destruction of cancer cells. [57–59]
It is worth mentioning that this study still has some limitations. First of all, as a retrospective study with a small sample, information bias and selection bias were difficult to avoid. Therefore, the results should be interpreted with caution. Secondly, inflammatory markers were non-specific and were influenced by a variety of factors, such as drugs, comorbidities, and infections. [60] Moreover, the optimal cut-off values for pre-treatment PLR and pre-treatment NLR were not known. In this study, the cutoff values of pre-treatment PLR and pre-treatment NLR were obtained according to effective statistical methods, but population-based research was still needed to verify. Last but not least, we failed to obtain enough follow-up data to evaluate the effect of arterial chemoembolization, inflammatory markers and pCR on DFS and OS. Therefore, large-scale multicenter study is needed for further confirmation.
In conclusion, this study demonstrated that neoadjuvant chemotherapy combined with arterial chemoembolization would not increase the adverse events of chemotherapy and postoperative complications in patients with LAGC. Arterial chemoembolization, pre-treatment NLR and pre-treatment PLR were independent predictors of pCR after neoadjuvant therapy. Therefore, arterial chemoembolization may be a safe and effective regime of neoadjuvant therapy for LAGC.