In the present study, we demonstrated that both CRP kinetics and initial apoA-I are useful biomarkers for patients with advanced NSCLC who have received first-line platinumed chemotherapy. CRP kinetics is more accurate than baseline/nadir CRP in predicting prognosis for NSCLC patients, and higher CRP levels accompanied lower apoA-I levels during treatment. Furthermore, we found that combining CRP kinetics with initial apoA-I may enhance prognostic prediction of patients with NSCLC more effectively compared to one variable analysis.
Inflammatory reaction plays a valuable function in tumor origination and development25. Circulating leukocytes and CRP always used to evaluating the inflammatory status. A large number of studies have proven that CRP, NLR, PLR, ALB, as poor prognostic indexes in cancers26-28. However, compared with other inflammatory predictors, both CRP and CRP kinetics are better independent predictors29,32-34. Multiple studies have confirmed that ApoA-1, a prognostic factor plays a role in anti-inflammatory and antioxidant activities in various tumor diseases30，37. As we all known, CRP is a strong prognostic predictor in many cancers. As reported previously 14, 33, patients without elevation of pretreatment CRP level have better prognosis than those with elevated pretreatment CRP level. Wilop et al. found that normalization of CRP during chemotherapy was associated with better prognosis15. Evidence indicates the prognostic importance of CRP kinetics in various solid cancers31-34. CRP kinetics, which comprises the effect of dynamic changes of CRP concentration, has been shown to be more informative than baseline CRP in predicting survival of patients with metastatic renal cell cancer and urothelial carcinoma25-27, whereas the prognostic value of CRP kinetics in NSCLC patients remains unknown. Additionally, apoA-I also could be an indicator of early epithelial ovarian 35 and pancreatic cancer 36. Others support this finding and suggest that patients without reduction of pretreatment apoA-I level have better prognosis than those with lower pretreatment apoA-I level 16. In hepatocellular carcinoma patients, they set up a new score based on serum apolipoprotein A-1 and CRP to predict the OS and DFS. In their retrospective analysis, they found the new score could accurately differentiate the prognosis of HCC patients and is a valuable predictor of OS and DFS 37. Hence, our study further to prove the predictive value of combination apoA-I and CRP on the survival of NSCLC patients.
In current studies, non-normalized CRP and lower apoA-I tended to be older, stage 4 and higher ECOG PS, while lower apoA-I also tended to be ever-smokers (Table 1), and non-normalized CRP more often in lower apoA-I group (Table 2). In univariate analysis, gender, smoking history, ECOG PS, stage, metastasis, baseline CRP and nadir CRP were shown to be associated with prognosis as well as CRP kinetics and initial apoA-I (Table 3). As the results show, TNM staging doesn’t have statistically significant both in univariate and multivariate. We studied patients with advanced NSCLC. If we include people with early stage non-small cell lung cancer, there may be a statistical difference. As mentioned in this paper37. Whereas, results from the Cox regression models for all patients showed a more accurate prognostic values of CRP kinetics and initial apoA-I even when adjusting for ECOG PS(Table 4).
Baseline and nadir CRP values of non-normalized CRP groups were significantly higher than those of normalized CRP group. Although both baseline and nadir CRP level were also independent predictors in multivariate analysis, CRP kinetics status was more informative in predicting survival when the predictive accuracy was evaluated between the model including CRP kinetics status or baseline/nadir CRP levels. Our results also demonstrated that CRP kinetics is more accurate than baseline/nadir CRP in predicting prognosis for NSCLC patients. It’s showing no difference with previous research31, 32.
Overall, CRP kinetics and apoA-I can be used as biomarkers for patients with NSCLC. Both biomarkers have been warranted to predict the risk of cancer, to assess tumor aggressiveness and to predict prognosis. The results of the current study indicate that serial measurements of CRP and initial apoA-I are useful to estimate the true status of tumor, to consider adverse effects of continuous cytotoxic chemotherapy, and both could be used as surrogate end points for patients with NSCLC.
The biological foundation for the predictive value of the dynamic changes of CRP and apoA-I level in NSCLC patients remain to be explicit. In an experimental study determined that circulating IL-6, which might be secreted from immune and stromal cells in response to tumor progression 38 or from cancer cells per se 39 or both. Afterwords it facilitates tumor cell proliferation and immune invasion 40. Production of CRP in the liver is strongly induced by pro-inflammatory cytokines such as IL-6 19，41. Hence, CRP could have a crucial role in the presence of systemic inflammatory response in NSCLC could be associated with poor prognosis. Furthermore, apoA-I, which decreased accompanied by elevated proinflammatory cytokines showed in previous studies 42. Increased expression of IL-6 stimulates the synthesis and secretion of non-pancreatic phospholipase A2 (sPLA2) in the liver during infection and inflammation 43. Recent studies have found that up-reguletion of sPLA2 reduced the density of apoA-I in transgenic mice 44. Therefore, decreased the level of apoA-I could be due to the subsequent acute-phase proteins stimulation of elevation of IL-6 during cancer progression. In the present study, we also found that increased CRP level was negatively correlated with lower apoA-I level in NSCLC. Therefore, increment of systemic inflammatory response, as evidenced by increase of serum CRP level and decrease of serum apoA-I level, may be associated with more aggressive behavior of NSCLC. The five-year overall survival rates of the patients with an unnormalized CRP and a low apoA-I level were lowest compared with the other four groups (shown in Figure 5), whereas, the patients with normal CRP and normal apoA-I had significantly higher survival rates among the five groups. These results have further affirmed the reversed relationship between CRP and apoA-I, moreover, they highlight the prognostic effect of the combining of CRP status and initial apoA-I.
In summary, CRP kinetics and initial apoA-I have an impact on survival in patients with advanced NSCLC treated by first-line platinumed chemotherapy. A normal in CRP level predicts better prognosis, while decrease in apoA-I predicts a worse prognosis. Both CRP and apoA-I, are readily available and inexpensive compared with many new biomarkers that have not been adopted in common use increases the prognostic significance of each alone. Therefore, the use of two determinations, such as CRP and apoA-I, increases the prognostic significance of each alone. Perhaps in non-small cell lung cancer, it is preferable to use a system of two or more determinants to create a prognostic tool for clinicians, as with the use of albumin and beta2-microglobulin in multiple myeloma in the International Prognostic Score (ISS). Similar to previous studies 29,37,45, it was a retrospective, single-institution study with relatively few patients. In order to make up for the deficiencies and improve the research design, the predictive value of CRP kinetics and initial apoA-I would be verified in multicenter prospective studies, with more patients and longer follow-up time.