Lung cancer is the most common malignant tumor in the world. Because of individual differences, the survival of lung cancer patients in the same stage also has a greater difference.
If the patient's survival can be predicted before treatment, it will be of considerable help to the patient's treatment choice. An appropriate treatment program can not only prolong the survival period of patients to the greatest extent, but also reduce the treatment cost of patients and reduce their economic burden. At present, there are some clinical tests, such as ctDNA and high-throughput sequencing technology, which can be used to help predict the survival of cancer patients[13–15]. But these tests are expensive and require long waiting times. Hematologic markers are readily available and inexpensive in clinical practice, and if they can be shown to predict patient survival, that would be good news for patients.
SUA/SCr and serum IL-6 have previously been shown to be predictive in a variety of diseases. Tong S et al. suggested that serum IL-6 level might be used as a potential prognostic biomarker for intravesical GEM in T1 NMIBC[16]. Gui-long Deng and Xing Sun et al. reported that elevated serum IL-6 levels were significantly associated with an increased risk of HBV-related HCC recurrence. The causal role of IL-6 in HCC recurrence can provide valuable information when selecting additional therapy following surgery[17]. The team of Giorgio Maria Saracco, Elisabetta Bugianesi, and Davide Giuseppe Ribaldone observed that changes in IL-6 during treatment can predict treatment response, thus helping clinicians to develop personalized treatment strategies[18]. Yongjun Wang et al. believed that SUA/SCr was positively correlated with the incidence of cardiovascular disease and was a poor prognostic factor[19]. The study of Songsomboon C et al. suggested that SUA/SCr plays a sensitive role in determining the association with Parkinson's Disease, and SUA/SCr may play a certain role in the pathogenesis of Parkinson's Disease[20]. Our study is the first to demonstrate that SUA/SCr and IL-6 can predict survival in lung cancer patients receiving concurrent chemoradiotherapy.
Il-6 is a 26kD protein composed of 184 amino acids. Il-6 can be synthesized and secreted not only by activated lymphocytes and mononuclear macrophages, but also by bone marrow cells and some tumor cells[21]. As an important medium in immune response, it has many biological activities. Il-6 is a pleiotropic cytokine that regulates a variety of cellular functions, including cell proliferation, cell differentiation, immune defense mechanisms and hematopoiesis. Il-6 is closely related to the occurrence and development of various tumors. It affects the progression of tumors by interfering with cell adhesion and activity, thrombosis, expression of tumor-specific antigens and proliferation of tumor cells. It also regulates a variety of cellular functions, including cell proliferation, cell differentiation, immune defense mechanisms and hematopoiesis[22, 23]. Uric acid is a major metabolite of birds and reptiles. It is slightly soluble in water and forms crystals easily. The main product in normal human urine is urea, containing a small amount of uric acid. Uric acid is the final product of purine metabolism. It is trioxy purine, and its alcohol form is weak acid[24, 25]. Creatinine is a metabolite of muscle tissue in the human body. Creatine in muscle tissue is dehydrated by non-enzymes into creatinine, which is excreted in urine through the glomeruli. Creatinine is a small molecule that can be excreted through glomerular filtration. Creatinine level is commonly used to evaluate renal function in clinic. Our study suggested that patients with larger SUA/SCr or IL-6 had shorter overall survival, while patients with smaller SUA/SCr and IL-6 had longer overall survival.
The reason for the difference in survival of patients with different SUA/SCr groups may be related to the high level of uric acid. High SUA levels have previously been identified as a risk factor for cancer morbidity and mortality. For example, Petersson et al. proposed in 1984 that increased uric acid was associated with increased cancer mortality[26]. Similarly, Strasak et al. conducted a large prospective study of European men and women and determined that elevated SUA was significantly associated with a higher risk of cancer mortality[27]. The reason may be that when uric acid enters cancer cells, it inhibits XOR expression and thus increases COX-2 levels. In addition, it can trigger inflammatory stress due to the effect of intracellular uric acid on COX-2 activation and production of reactive oxygen species (ROS)[28, 29]. Interestingly, our study did not reach the same conclusion when uric acid was analyzed separately. This is similar to Maciej Banach et al. 's conclusion that higher SUA/SCr increases all-cause mortality in elderly hemodialysis patients[30]. Their study concluded that SUA/SCr had better predictive value than uric acid and creatinine alone.
Previous studies have shown that IL-6 affects key parameters of tumourgenesis, increasing cell resistance to apoptosis, participating in cancer cell proliferation, angiogenesis, invasion, and reducing the ability of tumor cells to respond to anticancer therapies[31]. Meanwhile, previous studies have shown that long-term exposure to IL-6 reduces gp130 levels on T cells, reducing their ability to clear tumor cells[32–34]. Sharon S. Evans et al. suggested that IL6-activated transcription factor STAT3 drives angiogenesis by inducing tumor cells to express VEGF and fibroblast growth factor (bFGF), thereby supporting the vascularization required for tumor growth and metastasis[35, 36]. These may be the main reasons for the negative correlation between IL-6 index and survival of lung cancer patients.
Our research also has many shortcomings. First of all, we only included 147 patients from a single center, which may cause bias in patient selection. Secondly, our study only confirmed that SUA/SCr and IL-6 are predictors of survival of lung cancer patients, and further mathematical modeling and other studies are needed to enable clinicians to make more intuitive predictions. Finally, this is a retrospective study, and there may be data bias during the study, so we need to conduct some prospective studies to further prove our conclusions.