Change in the serum selenium level of patients with non-metastatic and metastatic non-small cell lung cancer (NSCLC) during radiotherapy as a predictive factor for survival

Cancer in general is the third most frequent cause of death worldwide and thus a serious medical problem, with lung cancer being one of the most commonly diagnosed cancers [1]. Lung cancer can be categorized into non-small cell lung cancer (NSCLC; around 85%) and small cell lung cancer (SCLC; 15%). Most patients are diagnosed in an advanced stage of disease, which limits the therapeutic options and overall survival (OS) of patients. Nearly 50% of all cancer patients undergo irradiation during their treatment course [2]. Despite an improvement in the efficacy of standard treatments like chemotherapy, surgery, tyrosine kinase inhibitors (TKI), and recently also immunotherapy [2‐6], lung cancer remains the leading cause of cancer deaths even in highly developed countries [1]. So far, not all lung cancer patients benefit from treatment at every stage of the disease. The development of resistance, adverse events, and unavoidable disease progression highlights the urgent need for novel diagnostic, prognostic, and therapeutic options for these diseases. To this end, reliable biomarkers that predict disease course and help to stratify patients in terms of those who are likely to experience a clinical benefit from certain therapies are urgently needed [7]. Regarding prognostic factors, cancer patients tend to have lower serum selenium levels than the general population [8, 9], making selenium a potential prognostic marker or therapeutic option. The importance of selenium for the antioxidant defense system and the immune response has been reported in many studies. Incorporated into proteins as selenocysteine, it influences the activity of a number of essential selenoproteins, such as members of the thioredoxin reductase, glutathione peroxidase, and iodothyronine deiodinase families, as well as many selenoproteins which directly affect the inflammatory response, apoptosis of cells, and status of reactive oxygen species (ROS) [10, 11]. Although the correlations between selenium status, cancer risk, and radiotherapy have been studied over the years, the results are heterogeneous, and underlying mechanisms of function remain unknown. Concerning lung cancer patients, a systematic review and meta-analysis demonstrated that selenium may be effective for lung cancer prevention and may reduce side effects of radiation. In addition, many in vitro studies have investigated the effect of selenium in irradiated breast cancer cell lines [12], normal as well as malignant human mononuclear blood cells [13], and lung cancer cells [14]. An increased cytotoxic effect of radiotherapy in malignant cells was observed during selenium substitution. In addition, dose-limiting side effects of anticancer treatments appear to be reduced in vitro. In vivo studies provide evidence of a benefit of selenium treatment during irradiation [15]. Therefore, this study aims to assess the serum selenium status of patients and correlates the results to survival in patients with histologically confirmed NSCLC prior to and during radiotherapy.

In this study, we describe significant associations of relative selenium deficiency and decline in selenium status with shorter survival odds in lung cancer. A proper supply of micronutrients, such as selenium, is essential for an efficient immune response, thereby reducing the risk of cancer incidence, fast progression, and adverse therapeutic effects. So far, little information exists about serum selenium levels upon radiotherapy. This study demonstrates the prognostic value of assessing changes in serum selenium levels for the first time. The selenium status at t0 was comparable between all groups and only patients with metastasized disease had almost no change during and after irradiation. The change in selenium levels between the start of treatment (t0) and the first timepoint after treatment (t1) was statistically significant in terms of the patients’ overall survival for the whole study cohort (models I–III); likewise, the patients with increased serum selenium levels during radiotherapy had the best OS (Fig. 3). In addition, significant associations with OS for the baseline selenium value t0 (univariate analysis) in patients with non-metastasized NSCLC were found. The changes in serum selenium between t0 and t1 (models I, III, IV) and also between t0 and t2 (models I–IV) were significant in terms of overall survival for metastatic cancer patients. To our knowledge, this is the first study to report altered selenium levels in lung cancer patients at different timepoints of radiotherapy and their association with the OS of patients.

The mean baseline serum selenium level of the study collective analyzed is lower when compared to healthy persons as references, e.g., from the participants of the EPIC cohort enrolled in Potsdam, Germany (median serum Se 80.0 µg/L, interquartile range 19.1 µg/L) [18]. A correlation between low serum selenium levels and cancer mortality has been reported in many entities, including liver, colorectal, and breast cancer [17, 19‐21]. Low serum selenium concentrations prior to therapy in stage I NSCLC patients were associated with decreased OS [22]. In addition, Lubiński and coauthors described very low selenium levels in laryngeal cancer patients at the time of diagnosis, which correlated with tumor progression and an increased risk of death [23]. Thus, serum selenium levels were of prognostic relevance prior to the initiation of anticancer treatment, especially in advanced stages of laryngeal tumors [23]. Due to malnutrition caused by invasive surgery and extended radiotherapy, also head and neck cancer patients have a lower selenium status [24]. The published reports confirm our results, since the patients of our study cohort with the lowest selenium levels between t0 and t1 or t0 and t2 had reduced OS. So far, the underlying mechanisms explaining why some cancer patients tend to have lower selenium levels have not yet been identified. However, it has been suggested that malignant disease might be associated with a low selenium status as a consequence of modified metabolism in cancer cells due to tumor-associated inflammation and reduced selenoprotein biosynthesis in the liver or due to predisposition [25, 26].

Moreover, other studies investigating the effect of irradiation on the selenium status in cancer patients including breast cancer patients reported decreased selenium concentrations in patients undergoing radiotherapy [27‐29]. In contrast, no change in selenium levels was detected in other studies [24, 30]. Importantly, a study in gynecological tumors indicated that supplemental selenium can be applied as adjuvant treatment in order to reduce the side effects of radiotherapy, without obvious effects on efficacy [31‐33]. However, these studies are not comparable to our investigation as the irradiated body area was much larger and the patients received other treatments prior to radiotherapy, or the authors assessed a different tumor entity. Zeng et al. analyzed NSCLC patients with brain metastases and found decreasing selenium levels [29]. Despite the same tumor entity being investigated, this study is different due to the distinct metabolism of the brain. In our study, the mean serum selenium concentration increased during therapy in the whole study cohort, in particular in patients with non-metastatic cancer, but only slightly in metastasized tumor patients. The underlying mechanisms causing the increased selenium levels in this subgroup have not been identified. The in vitro analysis of Chen and coauthors described a potentially antimetastatic influence of selenium on lung cancer cells [34]. Tian and coauthors investigated the effect of selenium nanoparticles on NSCLC cells during irradiation and found a decrease in cell migration and cell invasion and an increase in apoptosis of lung cancer cells [14]. These data suggest that selenium may reduce progression of the malignant disease and, in the case of our investigated study cohort, increase OS.

Regarding the limitations of our study, the German local citizen registration offices do not provide information about the cause of death, so lung cancer-specific mortality could not be estimated. The majority of patients presumably died as a result of their severe malignant lung disease. In addition, smoking tobacco can influence the selenium status [35]. However, this bias can be reduced to a minimum extent because more than 90% of our study participants had smoking habits. We analyzed the selenium value after the diagnosis of cancer and during the limited period of radiotherapy, so the impact of genetic and epigenetic factors is negligible during this short timespan. In addition, nutrition plays an important role in the serum status of trace elements. However, the participants of our study neither received oral nor parenteral selenium substitution. Moreover, most patients stayed in the hospital during the time of irradiation and thus received no additional selenium intake. In conclusion, selenium levels could be influenced by the malignant disease, as already considered by Lopez-Saez and coauthors [25], or deficits may have pre-existed as a risk factor for lung cancer. Our study extended this knowledge by investigating whether changes in selenium levels during treatment occur and could predict OS.

The present study suggests that the change in serum selenium levels during radiotherapy might be a predictive factor for OS in NSCLC patients. Increasing selenium levels appeared to be associated with improved survival, in particular of metastatic NSCLC patients. As a result, supplementation of selenium in lung cancer patients should be discussed and respective interventional trials require consideration because patients with metastatic disease may benefit from higher selenium levels. In the future, additional independent studies are needed to assess changes in selenium status with or without adjuvant selenium supplementation in larger patient cohorts with respect to survival. This would improve the database regarding the potential importance of selenium in cancer treatment for predicting prognosis during radiotherapy and for testing the potentially beneficial effects of adjuvant supplementation with a cost-effective and safe micronutrient.