Lung cancer has the highest morbidity and mortality in China (1); 80-85% of patients with lung cancer had non-small cell lung cancer (NSCLC), and the majority were advanced at the time of initial diagnosis. Tumor-associated anemia is one of the common concomitant diseases of malignant tumors (2). Tumor-associated anemia production can be caused by a variety of factors, including tumor factors or tumor treatment factors. Tumor-associated anemia is common in patients with lung cancer and is often dramatically increased due to cancer therapy, especially platinum chemotherapy (3-7). Tumor-associated anemia can cause a variety of clinical symptoms, seriously reduces the quality of life of patients, affects the patient's tolerance to treatment, and reduces tumor tissue sensitivity to treatment (8).

The relationship between tumor-associated anemia and lung cancer prognosis has been the focus of clinicians. A recent meta-analysis of 23 studies that included 10,612 patients showed that preoperative anemia was a prognostic factor of lung cancer (9), as compared with LC patients without anemia, those with pre-operative anemia were at a 1.6-fold greater risk of death (summarized HR=1.58; 95% CI, 1.44-1.75). Zhang YH (10) reported that patients with normal pre-treatment hemoglobin (NPHb) levels had a greater chance of surviving for longer period, than did patients with low pre-treatment hemoglobin (LPHb) levels (HR=2.05; 95% CI, 1.63-2.57; P<0.001); Mandrekar et al (11) reported that patients with low Hgb levels had significantly worse TTP and OS. Wan et al (12) report that compared to patients with a low Hb change (|ΔHb|≤2.6), those having a |ΔHb|>2.6 exhibited a significantly shorter survival [hazard ratio=1.40, 95% confidence interval 1.31-1.50, P=4.5x10(-22), Plog rank=1.6x10(-39)]. Aoe et al reported that anemia is a prognostic factor of patients with lung cancer at first hospital visit (13), survival was significantly shorter in 298 patients with anemia (median survival time (MST): 7.5 months) compared with 313 patients without anemia (MST: 11.8 months, P<0.0001). The majority of studies have shown that anemia is a prognostic factor of lung cancer, but controversy still exists; several studies have shown that anemia is not associated with the prognosis of lung cancer (14,15). In previous studies on the prognoses of anemia and lung cancer, anemia diagnostic criteria, and detection methods, the results may be biased due to the inconsistency of anemia research subjects. Therefore, in our single-center study, the baseline anemia of 4,874 patients with stage IV non-small cell lung cancer was used as the research object to minimize the interference of related factors.

This study retrospectively analyzed the incidence and grade of baseline anemia in 4,874 patients with stage IV non-small cell lung cancer in China. The relationship between baseline anemia and clinicopathological characteristics and their effects on prognosis were analyzed to further guide the treatment of lung cancer.

Our study included 4,874 patients with stage IV NSCLC. This was the largest sample size of a research on anemia in NSCLC in China. The prevalence of baseline anemia was 32.09% with a mean Hb level of 123.32±20.31 g/l, of which 19.08% had mild anemia, 10.79% had moderate anemia, 1.91% had severe anemia, and 0.31% had life-threatening anemia. Most patients with baseline anemia showed mild to moderate anemia. The incidence of baseline anemia was slightly lower than that reported in other countries based on European populations (3) but slightly higher than that reported for American populations (6). ECAS is a prospective, observational, and epidemiological survey of the anemia in the European region. At ECAS enrollment, 37.6% of lung cancer patients had Hb levels of <12.0 g/dl (3). In a retrospective, observational study on anemia in patients undergoing chemotherapy for solid tumors in the United States, 7,001 patients with NSCLC were enrolled. At baseline, 16.1% of the patients were anemic with Hb levels of <11.0 g/dl, and 33.6% had Hb levels of <12 g/dl; the mean (SD) Hb at baseline was 12.7 (1.8) g/dl (6). The difference in results may be related to the different definitions of anemia. Therefore, a standardized and uniform anemia definition may lead to standardized diagnosis and treatment.

Aoe et al reported that in 611 cases of lung cancer in Japan, a significant correlation was found between anemia and age and Eastern Cooperative Oncology Group (ECOG) scores; however, anemia was not correlated with sex, histological type, clinical stage, or serum lactate dehydrogenase (13). The results of our study showed that female patients with baseline anemia were fewer than male patients with baseline anemia (36.85 vs. 25.56%, P<0.001). Compared with younger patients, patients who are >60 years old had higher prevalence of baseline anemia (34.41 vs. 29.31%, P<0.001). The prevalence of baseline anemia was highest in patients with squamous cell carcinoma (49.67%), followed by patients with other NSCLC types (36.93%). Patients with adenocarcinoma had the lowest prevalence of baseline anemia (29.34%), P<0.001. Our study shows that the proportion of non-smokers is relatively high compared with other study (18), which may be related to the population of the study. A data from the Asian population published by Zhang shows that the proportion of non-smokers is 42.8% (10), the proportion of non-smoking patients in our study is similar to Zhang's study. In addition, the proportion of female patients in our study is relatively high, while the proportion of female patients who smoke in China is very low; the proportion of patients receiving Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) targeted therapy in our study is higher, and the dominant population of EGFR-TKI targeted therapy is non-smokers. Patients with smoking history had higher baseline anemia than nonsmokers (38.97 vs. 27.38%, P<0.001). The results were consistent with those obtained in a retrospective study involving 416 NSCLC cases reported by Zhang et al in Henan, China (10). The study further confirmed the basic characteristics of anemia in Chinese lung cancer patients. The results of our study showed that patients without bone metastases had less baseline anemia than those with bone metastases (34.38 vs. 30.11%, P=0.002), considering that bone marrow invasion in patients with bone metastasis leads to a decrease in hematopoietic function.

According to previous studies on anemia and lung cancer prognosis, radiotherapy and chemotherapy are the main methods used to treat lung cancer (10,12,13,18,19). In the past decade, targeted therapy and immunotherapy have changed the treatment mode of advanced lung cancer. In our study, the proportions of patients undergoing chemotherapy, targeted therapy, radiotherapy and immunotherapy were 70.29, 58.06, 33.38 and 4.19%, respectively. The proportion of patients undergoing targeted therapy was higher, and immunotherapy was included in the study; our research reflects the current treatment model for advanced lung cancer (20).

A meta analysis of 23 studies including 10,612 patients showed that preoperative anemia was a prognostic factor of lung cancer (9); patients with preoperative anemia had reduced OS after lung surgery. For patients with advanced lung cancer, the opportunity for surgery is lost; so, the result helps guide patients who will undergo surgery for treatment. Other studies also showed that anemia is associated with the prognosis of lung cancer, but the sample sizes are relatively small or they included multiple cancers (10-13). The evidence from studies investigating the relationship between anemia and the progression of NSCLC remains controversial, as several studies have shown that anemia is not associated with the prognosis of lung cancer (14,15). Our study is a single-center study with a large sample size that was performed in the real world in China. We analyzed the relationship between baseline anemia and prognosis in 4,874 patients with IV non-small cell lung cancer. Univariate analysis results showed that patients without baseline anemia had longer OS than those with anemia (median OS: 28.0 vs. 17.4 months, P<0.001). Further multivariate analysis revealed that baseline anemia was an independent prognostic factor in patients with stage IV NSCLC. Our conclusion is consistent with the relevant research results (9-13). The reason for the shortened survival of patients due to tumor-associated anemia is the decreased sensitivity to treatment and tolerance to treatment. According to the anemia grade, we divided the patients into three groups, namely, anemia grades 0, 1-2, and 3-4. With rising anemia grade, the OS became shorter. The patients with anemia grade 0 had the longest OS (median OS: 28.0 months), followed by patients with anemia grades 1 and 2 (median OS: 17.5 months). The patients with anemia grades 3 and 4 had the shortest OS (median OS: 8.6 months), P<0.001. Multivariate analysis showed that baseline anemia grade was also a prognostic factor of stage IV NSCLC patients. Results further confirmed the importance of baseline anemia for NSCLC, which requires attention and timely treatment (21). Treatment of tumor-associated anemia include the correction of nutritional deficiencies, use of intravenous (IV) iron, erythropoietic stimulating agents (ESAs), and blood transfusions (2), the use of ESAs is still controversial due to its security issues. The results of a phase III clinical study on ESAs treatment showed that Darbepoetinalfa dosed to a 12.0-g/dl Hb ceiling was noninferior to placebo for OS and PFS and significantly reduced odds of transfusion or Hb≤8.0 g/dl in anemic patients with NSCLC receiving myelosuppressive chemotherapy (21). The early treatment of anemia is very important. Whether management of anemia can improve the survival of patients, it may be an aim of future studies.

Our study had some limitations. The major limitation is its retrospective nature. Moreover, the study is a single-center study. However, as the largest sample size research on anemia in NSCLC, our results are meaningful and can serve as a guide for the treatment of NSCLC patients with anemia in China. In the future, multi-center prospective studies are needed.

The study showed that the prevalence of baseline anemia was highest in patients with stage IV NSCLC who are men, >60 years old, with smoking history, with squamous cell carcinoma, and with bone metastases. Baseline anemia and anemia grading were independent prognostic factors in patients with stage IV NSCLC.