Recent promising results of new systemic treatments, including tyrosine kinase inhibitors and immunotherapy, have enabled patients with advanced HCC to receive multiple systemic treatments in sequence. Regorafenib, an oral multikinase inhibitor, demonstrated survival benefit over placebo in the phase 3, double-blinded RESORCE study. An exploratory analysis in the RESORCE trial revealed that sorafenib-regorafenib sequential treatment could provide extended survival (> 2 years) to patients with advanced HCC who did not benefit from locoregional theray. After adopting of regorafenib as an initial second-line agent, several real-life reports with good results of regorafenib treatment when progressed on sorafenib were published. Recently, several novel therapeutic agents as second-line therapies after sorafenib failure have shown promising results. Several treatment options are currently available for patients who failed on sorafenib treatment. Therefore, it is important to identify factors to predict treatment response or prognosis.
The present study investigated the predictive factors using systemic inflammatory markers by evaluating the efficacy and safety of sorafenib-regorafenib sequential therapy in patients with advanced HCC. This study revealed that regorafenib was well tolerated and favorable safety in patients with advanced HCC. Reforafenib demonstrated an objective response rate (ORR) of 11.8%, DCR of 60.9%, a median PFS of 3 months, and a median OS of 8 months. These results are similar to those of previous studies . We investigated the prognostic role of systemic inflammatory markers including SII and found that the SII was an independent predictive factor associated with OS. High SII levels at initiation of regorafenib were associated with poor survival.
Previous studies have demonstrated association of inflammation markers with cancer prognosis and elevated SII is associated with poor OS or PFS of patients with cancers. In HCC, many studies have reported relationship between SII and prognosis of patients treated with various treatments [20–22]. As a combined score based on peripheral platelet, lymphocyte and neutrophils counts, the predictive value of SII for survival may be explained by the role of these immune cells. High SII usually results from thrombocytosis, neutrophilia and lymphopenia, suggesting a decreased immune response. Inflammation plays essential role in the development of cancer and promotes all stage of tumor progression. Cancer cells are surrounded by stromal cells and immune cells to form tumor microenvironment . Increasing evidences have demonstrated that neutrophilia and thrombocytosis are associated with cancer progression [24–27]. Neutrophils play pro-tumoral roles through multiple mechanisms. Neutrophils can enhance cancer cell invasion, proliferation and metastasis by releasing inflammatory mediators such as neutrophil elastase, matrix metalloproteinase-9, and interleukin-8. Neutrophils secrete the pro-inflammatory factors in the tumor microenvironment, resulting in lymphocyte apoptosis and immunosuppression . Platelets act as multifunctional cells participating in hemostasis, tissue generation and immune response as well as in cancer growth, invasion, and metastasis. Growing evidence had demonstrated that platelets facilitate cancer progression and have a well-defined role in cancer invasion and metastasis [29, 30]. Conversely, lymphocytes are known to play a fundamental role in cell-mediated immune response against cancer. Lymphopenia, which reflects the decreased immune surveiilance against cancer, has been reportedly to be associated with poor survival in various solid tumors [31–33].
The AFP level has been used as a diagnostic criterion and is well known to be correlate with HCC prognosis. High AFP levels are associated with larger tumor, bilobar involvement, vascular invasion, poorly differentiated histology and decreased survival . The AFP level has been included in several HCC prognostic scoring systems [35–37]. High AFP levels are recognised as a poor prognostic factor, and AFP level higher than 400 ng/mL has been consistently associated with poor prognosis in several HCC treatments [38, 39]. These results may be elucidated from the relationship between AFP level and VEFGR expression level. VEGF and VEGFR-2-mediated signaling play important roles in angiogenesis and contribute to tumor growth in various cancers, including HCC [40, 41]. Increased AFP levels have been associated with increased VEGFR expression and increased angiogenesis in HCC [42, 43]. In this study, patients with high AFP and SII showed poor prognosis compared with those with low AFP level and SII. However, no correlation was found between the AFP and SII.
This study has several limitations. First, this study was a retrospective, single-center study with a small number of patients. Second, cutoff value of SII is arbitrary and validation of the cutoff value was not performed. Third, we did not conduct additional experiments to identify the underlying mechanism of the relationship between the SII and survival in patients with advanced HCC received regorafenib treatment. However, despite these limitations, this is the first study according to our knowledge to suggest that SII alone can predict the prognosis of patients with advanced HCC who received sorafenib-regorafenib sequential treatment.