Anemia of chronic disease (ACD) is a common complication among patients with malignant tumors, and its related clinical symptoms can reduce their quality of life (Expert committee on tumor-associated anemia of Chinese Society of Clinical Oncology, 2015; Wang et al., 2018). Clinically, many patients with advanced malignant tumors who cannot tolerate radiotherapy and chemotherapy are more likely to be complicated by ACD. The goal of treatment for these patients is mainly to improve their quality of life and reduce the need for blood transfusion. Therefore, it is of great clinical significance to explore effective treatment strategies for malignant tumors complicated by ACD. Some studies have shown that the use of EPO can reduce the transfusion needs of ACD patients, but the efficacy is still poor in at least one-third of ACD patients (Expert committee on tumor-associated anemia of Chinese Society of Clinical Oncology, 2015). Thalidomide can play its role in inhibiting tumor angiogenesis and nuclear transcription factors, inducing tumor cell apoptosis, and regulating expressions of vascular endothelial cell adhesion molecules (Du et al., 2005). Furthermore, it has been suggested that thalidomide is effective in the treatment of ACD (Zhong et al., 2012), so thalidomide combined with EPO is expected to further improve anemia in ACD patients. Thus, this study analyzed the clinical efficacy of thalidomide combined with EPO and iron sucrose in the treatment of malignant tumors complicated by ACD, and the report was presented as follows.

1 Materials and Methods

1.1 Subjects

From January 2017 to January 2019, 60 patients with malignant tumors complicated by ACD who were hospitalized in our hospital were enrolled, and they met the diagnostic criteria of ACD in the 2007 Diagnostic and Therapeutic Criteria for Hematopathy by Zhang Zhinan (Zhang, 2007). There were 26 males and 34 females, with the age range of 32-78 years. For the disease types, there were 14 with breast cancer, 9 with lymphoma, 7 with lung cancer, 7 with colorectal cancer, 5 with endometrial cancer, 4 with pancreatic cancer, 3 with gastric cancer, 3 with liver cancer, 3 with ovarian cancer, 3 with cervical cancer, and 2 with esophageal cancer. This study was approved by the Ethics Committee of Heilongjiang Provincial Hospital and conducted in accordance with the standards of the Declaration of Helsinki.

1.2 Methods

All enrolled patients were randomly assigned in a 1:1:1 ratio to three groups, and the following treatment regimens were performed. Treatment group 1: thalidomide (produced by Changzhou Pharmaceutical Factory Co., Ltd.) 100/d, continuous oral administration; EPO (produced by Chengdu Diao Jiuhong Pharmaceutical Factory Co., Ltd.) 150 IU/kg, subcutaneous injection, 3 times a week; iron sucrose injection (produced by Nanjing Hencer Pharmacy Co., Ltd.) 100 mg, intravenous injection, once a week; Treatment group 2: EPO 150 IU/kg, subcutaneous Injection, 3 times a week; iron sucrose injection, 100 mg, intravenous injection, once a week; control group: EPO 150 IU / kg, subcutaneous injection, 3 times a week; polysaccharide iron complex (produced by Qingdao Growful Pharmaceutical Co., Ltd. of Shanghai Pharmaceuticals Holding Co., Ltd.) 150mg, orally, once a day. If ferritin was >800 ng/ml, iron should be discontinued; if hemoglobin (HGB) was >110 g/L, EPO should be discontinued.

1.3 Efficacy evaluation

By reference to relevant literature, being effective: HGB level was increased by more than 15 g/L compared with baseline level (no blood transfusion 30 d before treatment and during treatment) or HGB returned to normal (female: HGB>110 g/L; male: HGB>120 g/L); ineffective: HGB level was increased by ≤15 g/L compared with baseline level or decreased. The response rate among the three groups after 8 weeks of treatment was compared.

1.4 Evaluation of adverse reactions

Adverse reactions during the treatment were observed and recorded to evaluate the safety.

1.5 Statistical methods

Statistical analyses were performed using SPSS19.0 software. The count data were compared with χ2 test, and the measurement data were compared by t test. P<0.05 was considered statistically significant.

2 Results

2.1 General data

In this study, 60 patients were enrolled, and there were no significant differences in age, gender, and HGB levels among the three groups (P>0.05) (Table 1).

Table 1 Comparison of baseline data between the treatment groups and control group (mean ± standard deviation) Note: p < 0.05 for comparisons among the three groups

2.2 Treatment outcomes for the three groups

For the group receiving thalidomide combined with EPO and intravenous injection of iron sucrose, HGB was (82.2±10.6) g/L before treatment, and (104.8±10.9) g/L after treatment, t = 4.7, and P <0.05 indicated statistically significant difference; for the group receiving EPO combined with intravenous iron supplementation, HGB was (84.8±12.9) g/L before treatment, and (100.3±11.8) g/L after treatment, t = 2.8, and P <0.05 indicated that the difference was statistically significant; for the group receiving EPO combined with oral iron supplementation, HGB was (80.6±9.7) g/L before treatment, and (92.4±9.6) g/L after treatment, t = 2.7, and p<0.05 indicated that the difference was statistically significant. There was significant difference in HGB between the treatment group 1 and the control group after treatment, p<0.05. The treatment group 1 had higher response rate after treatment, and the difference was statistically significant compared with the control group, p<0.05. Details were shown in Table 2. 

Table 2 Comparison of the therapeutic effects between the treatment groups and the control group after treatment Note: * P < 0.05 compared with the control group

2.3 Adverse reactions

All subjects had no serious adverse drug reactions. In the treatment group 1, there were 3 with numbness of limbs and 2 with slight increase in alanine aminotransferase (ALT); in the treatment group 2, there were 1 with slight increase in ALT and 1 with mild urticarial; for the control group, there was 1 with mild skin reaction at the injection site. After symptomatic treatments, the above adverse reactions were improved, and no drug discontinuation was reported due to adverse reactions.

3 Discussion

Anemia of chronic disease (ACD), also known as anemia of inflammation (AI), is one of the most common complications of advanced malignant tumors, adversely affecting the quality of life of patients. Therefore, it is imperative to choose a safe and effective method to treat anemia (Gao et al., 2009). The pathogenesis of ACD is very complex and remains unclear at present. Some studies have shown that hepcidin, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) play an important role in the pathogenesis of ACD (Sharma et al., 2008; Uach et al., 2010; Kalyani and Jamil, 2015; Liu et al., 2015). Studies have demonstrated that thalidomide has functions of anti-angiogenesis and regulating IL-6 and TNF-α, and can be used as an adjuvant for anti-tumor therapy in most patients with intermediate and advanced malignant tumors (Zhang et al., 2016; Chen, 2019). Data in this study suggested that after treatment with thalidomide combined with EPO and intravenous injection of iron sucrose in patients with malignant tumors complicated by ACD, HGB was increased from (82.2 ± 10.6) g/L to (104.8 ± 10.9) g/L, with the response rate being up to 75%, and the efficacy was significantly higher than that of the group receiving EPO combined with oral iron supplementation, and the difference was statistically significant. The response rate was also higher than that of the group receiving EPO combined with intravenous iron supplementation (75.0% vs. 50.0%), but there may be no statistical difference due to sample size. Therefore, thalidomide combined with EPO and intravenous iron supplementation could further improve the anemia in patients with malignant tumors complicated by ACD.

EPO treatment is mainly given to patients with malignant tumors complicated by ACD, but there are still some differences in how to give iron supplement. Currently, related studies at home and abroad have shown that the main pathogenesis of ACD is related to the shortening of red blood cell survival, the reduction of stored iron release in monocyte-macrophage system (MMS) and the decrease in reactivity of bone marrow to EPO (Weiss et al., 2019). Hepcidin is a small-molecule peptide hormone synthesized by hepatocytes, and it is involved in iron metabolism, mainly binds to iron transporters, blocks intestinal iron absorption and causes iron retention in MMS, thus leading to iron-restricted erythropoiesis (Detiavaud et al., 2005). Therefore, the intestinal absorption rate is low for oral iron supplements, and it can be combined with extra-gastrointestinal iron supplementation when necessary (Ye et al., 2009). This study suggested that for patients with malignant tumors complicated by ACD, the improvement of anemia in the group receiving EPO combined with intravenous iron supplementation was better than that in the control group [(100.3 ± 11.8) g/L vs (92.4 ± 9.6) g/L], and the response rate was also higher than that in the group receiving EPO combined with oral iron supplementation (50.0% vs. 40.0%), but there may be no statistical difference due to sample size.

In conclusion, this study showed that thalidomide combined with EPO and intravenous iron supplementation could effectively improve the anemia in patients with malignant tumors complicated by ACD, with mild adverse reactions. Although the sample size is small, and the experiment may have deviations, it also provides a good idea for clinicians in treating patients with malignant tumors complicated by ACD.

Authors’ contributions

Liru Wang wrote and translated the manuscript. Yinghui Wang read and approved the final manuscript. Menglin Liu, Ying Du, Shuang Sun , Wei Liu, Xia Dong, Enhong Shi ,Jing Zhao and Wenxin Wang collected materials. All authors read and approved the final manuscript.

Acknowledgments

This work was supported by Science and Technology Plan of Heilongjiang Health and Planning Commission (2017-476).

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