Cervical cancer is one of the most common gynecological malignant tumors, with 604,000 new cases and 342,000 deaths worldwide reported in 2020 (1). The standard treatment mode of early-stage (FIGO stage IA-IB1) patients is radical hysterectomy, lymph node dissection, and/or radiotherapy, and locally advanced stage (FIGO stage IB2-IVA) patients mainly receive platinum-based concurrent chemoradiotherapy (2). The overall incidence of genitourinary complications is reported to be between 17 and 40% in patients with concurrent chemoradiotherapy, while acute toxicity of grades 3–4 occurs in 17.1% of patients with concurrent chemoradiotherapy (3). Acute toxic reactions caused by concurrent chemoradiotherapy often require dose modifications or radiotherapy treatment suspension, which could potentially impair the curative effects of concurrent chemoradiotherapy and prolong the length of stay in the hospital. Previous studies demonstrated that intensity modulation radiotherapy significantly reduced the level of gastrointestinal and hematological toxicity in patients with cervical cancer in comparison to conventional radiotherapy (4, 5). It is imperative to search for an effective strategy to decrease the incidence of acute side effects during concurrent chemoradiotherapy in patients with cervical cancer.

Selenium is an essential trace element and has extremely important biological functions in human health. Previous studies have demonstrated that selenium compounds can enhance the effect of radiotherapy and chemotherapy (6–8). Several studies have revealed that selenium supplementation may decrease the toxicity of chemotherapy and radiotherapy (9–11). However, these studies have been constrained by the limited number of patients included and the lack of randomized controlled clinical trials, and the association between selenium supplementation and acute toxic reactions and clinical outcomes in patients with locally advanced cervical cancer treated with concurrent chemoradiotherapy remains unclear. Therefore, we conducted a randomized, placebo-controlled trial to assess whether adding selenium yeast to platinum-based concurrent chemoradiotherapy would decrease acute side effects during treatment and improve efficacy compared with placebo for patients with stage IIB cervical cancer.

We conducted a randomized, double-blind, and placebo-parallel controlled clinical trial to evaluate the effects and safety of Se supplementation on concurrent chemoradiotherapy in patients with stage IIB cervical cancer. This study was approved by the Ethics Committee of the Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, and all patients signed informed consent forms to participate in the study. The trial was registered at https://www.chictr.org.cn/listbycreater.aspx (ChiCTR2100043379).

Selenium is an essential trace element that is fundamentally important to human health. Epidemiological studies demonstrated that salt fortified with selenium as sodium selenite decreased the incidence of hepatocellular cancer by 35% compared to the control group (13). The Nutritional Prevention of Cancer Trial was the first double-blind, placebo-controlled intervention trial to assess whether selenium supplementation could reduce the risk of cancer. Selenium supplementation showed effects of 50% lower total cancer mortality (p = 0.002) and 37% lower total cancer incidence (p = 0.001) (14). Selenium deficiency also increases the risk of cervical cancer (15). On the other hand, selenium can reduce the harmful toxicities of radiotherapy and chemotherapy without compromising efficacy (8). In this study, we found that selenium supplementation decreased the incidence of grade 3 myelosuppression (p = 0.034) but had no effect on the incidence of grade 0–1 myelosuppression, with 26 (52%) in the experimental group and 25 (46.3%) in the control group (p = 0.695). Selenium supplementation did not decrease the incidence of thrombocytopenia in patients with cervical cancer between the two groups. However, in a subgroup of patients with highly differentiated cervical cancer, a significant difference in platelet toxicity was observed, with 7 of 13 (53.8%) in the experimental group and 15/19 (78.9%) in the control group (p < 0.01). An earlier in vitro study showed that supplementation with Se yeast alone or in combination with chemotherapeutic drugs could induce apoptosis in several tumor cell lines (16). In our study, the ORR between the experimental group and the control group was not significantly different (96% vs. 94%, p = 0.47), indicating that selenium supplementation has a negligible impact on the efficiency of chemoradiotherapy in cervical cancer. To the best of our knowledge, this is the first clinical trial exploring the role of the addition of selenium in the treatment of patients with cervical cancer. Although several studies have confirmed that selenium supplementation enhances the efficacy of radiotherapy and chemotherapy (17), another phase II clinical trial revealed the opposite result in patients with stage III and stage IV head and neck squamous cell carcinoma treated with selenomethionine combined with concurrent chemoradiotherapy and simple concurrent chemoradiotherapy. It was found that there was no significant difference in CR, overall survival, and progression-free survival between the two groups (17). Although the short-term efficacy of selenium yeast combined with concurrent chemoradiotherapy for cervical cancer has not improved, our data showed that the incidence of myelosuppression in the experimental group was lower than that in the control group. Similar effects have been observed by Katya’s team, who noticed that there was no increase in the toxicity of platelets, white blood cell count, neutrophils, hematocrit, and hemoglobin during the selenium supplementation period in leukemia/lymphoma patients (18). Moreover, another study has shown that the addition of 500 μg/day sodium selenite during radiotherapy can reduce the number and severity of diarrhea caused by radiotherapy (10). Recently, a Japanese study revealed that serum selenium predicts achievement of full-dose cisplatin in concurrent chemoradiotherapy for locally advanced head and neck squamous cell carcinoma. Selenium deficiency before treatment was independently associated with poor compliance with cisplatin (19). Collectively, these studies support our findings that selenium supplementation ameliorates the toxic effects of chemoradiotherapy without extra gastrointestinal side effects, providing a new strategy to improve the tolerance and compliance of patients to chemoradiotherapy.

Current studies indicate that radiation therapy and cisplatin induce lipid peroxidation and ferroptosis in cancer cell lines, human cancer samples, and the renal proximal tubules of mice (20, 21). Polyunsaturated fatty acids participate in the formation of essential lipid products that play a crucial role in activating or inhibiting platelet function (22). The platelet membrane structure is very complex with a large number of lipids, making it very sensitive to radiation-induced lipid peroxidation. Recently, a study indicated that although the exposure dose was below the limit, medical workers exposed to low-dose ionizing radiation for a short period of time might have increased first and then decreased platelets (23). Hemoglobin, heme, and hemin produced by old red blood cells trigger ferroptosis in platelets (24). GPX4 is a selenoprotein that utilizes reduced glutathione to convert lipid hydroperoxides to lipid alcohols, thereby alleviating lipid peroxidation and inhibiting ferroptosis. Selenium supplementation can activate GPX4 activity and alleviate ferroptosis inducer RSL3 and erastin-induced lipid oxidation in the retina and heart samples of mice (unpublished data). Hence, we hypothesize that selenium supplementation ameliorates the toxic effects of chemoradiotherapy on platelets by activating GPX4 and mitigates lipid peroxidation, which needs further study in the future.

Although we have provided evidence demonstrating that selenium supplementation can reduce side effects but does not compromise the therapeutic effect of chemoradiotherapy, the molecular mechanism remains unknown. Our trial had several limitations, including that the sample size was limited and the dosage and duration of selenium supplementation were not optimized but can be improved by longer and larger trials in the future. We will continue to follow up with our participants for a much longer time to observe the effect of selenium supplementation on the survival time and gastrointestinal side effects of our patients with cervical cancer.

This prospective study demonstrated that selenium supplementation could alleviate the hematologic toxicity of concurrent chemoradiotherapy, but no adverse effects were observed in the treatment of cervical cancer. Selenium supplementation does not compromise the therapeutic effect of chemoradiotherapy and could be a promising therapeutic strategy to protect against chemoradiotherapy-induced side effects.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Ethics Committee of the Central Hospital of Enshi Tujia and Miao Autonomous Prefecture. The patients/participants provided their written informed consent to participate in this study.

LL, CH, and ZZ: conception and design. QH, MY, XL, and PL: administrative support. BP, XF, XH, ZY, JC, DH, GS, and LW: provision of study materials or patients. QH and MY: data analysis and interpretation. MY, BP, QH, and CH: manuscript writing. All authors contributed to the article and approved the submitted version.

This work was supported by the National Natural Science Foundation of China (No. 81660503, 82160490); Health Commission of Hubei Province Scientific Research Project (WJ2021F095); Natural Science Foundation of Enshi Tujia and Miao Autonomous Prefecture Government (E20170002, D20210033).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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