TITLE: Selenium in Radiation Oncology—15 Years of Experiences in Germany 

  ABSTRACT:
Introduction: Se measurement and supplementation in radiation oncology is a controversial issue. The German Working Group Trace Elements and Electrolytes in Oncology (AKTE) has conducted a number of studies on this issue, which are summarized in this review. Strategies have been tested and developed, aiming to stratify the patients with a potential need for supplemental Se and how best to monitor Se supplementation with respect to health effects and risks. Methods: We analyzed blood and tissue Se-levels of different tumor patients (n = 512). Two randomized phase III clinical studies were conducted for testing a potential radioprotective effect of supplemental Se during radiation therapy in patients with uterine cancer (n = 81) and head and neck tumor patients (n = 39). Results: A relative Se deficit in whole blood or serum was detected in the majority of tumor patients (carcinomas of the uterus, head and neck, lung, rectal or prostate cancer). In prostate cancer, tissue Se concentrations were relatively elevated in the carcinoma centre as compared to the surrounding compartment or as compared to tumor samples from patients with benign prostatic hyperplasia. Adjuvant Se supplementation successfully corrected Se-deficiency in the patients analyzed and decreased radiotherapy-induced diarrhea in a randomized study of radiotherapy patients with carcinomas of the uterus. Survival data imply that Se supplementation did not interfere with radiation success. Some positive effects of supplemental Se in the prevention of ageusia (loss of taste) and dysphagia due to radiotherapy were noted in a second randomized trial in patients with head and neck cancer. We have not observed any adverse effects of supplemental Se in our studies. Conclusions: Se supplementation yielded promising results concerning radioprotection in tumor patients and should be considered as a promising adjuvant treatment option in subjects with a relative Se deficit.

BODY.1. INTRODUCTION (WHY SHOULD A GERMAN RADIATION ONCOLOGIST BE INTERESTED IN SE):
Supplementation with the essential trace element Se is increasingly recognized as a promising adjuvant treatment option by radiation oncology expert groups. Cancer-preventive and cytoprotective activities of supplemental Se have been reported in a number of animal cancer models and clinical trials. A sufficiently high Se intake is needed to support the regular biosynthesis of selenoproteins, which are centrally implicated in redox regulation and antioxidant functions. By these and additional mechanisms, selenoproteins protect membrane integrity, contribute to regular energy metabolism and prevent DNA damage [1,2,3,4].  Compared to the USA, the population in many European countries including Germany needs to be considered as slightly Se deficient. Soil Se contents differ strongly around the world and therefore also the Se content of the food obtained from different soils reflects this difference [3,5]. Experimental evidence from preclinical and human studies indicate that a low Se status may augment radiation-induced damage while a sufficiently high Se supply might elicit protective activities and reduce the risk of side effects from the therapeutic radiation exposure (Table 1) [6,7,8,9,10,11,12,13,14,15,16].  For these and other reasons, the popularity of self-medication with supplemental Se is increasing in both healthy and diseased subjects, especially in cancer patients who hope to improving their quality of life, reducing side-effects during therapies, strengthening their immune system and supporting their recovery. However, such self-treatment is usually not reported to the treating oncologist, causing some degree of uncertainty during therapy [17].  For obvious reasons, the radiation oncologist is mainly interested in whether supplemental Se may affect therapeutic effects by either altering the sensitivity of healthy tissue to the damaging radiation or by even improving the curative effects of therapeutic radiation on the malignant tissue.

BODY.2. SE MEASUREMENT IN TUMOR PATIENTS:
The German Working Group Trace Elements and Electrolytes in Oncology (AKTE, Bielefeld, Germany) has performed several studies in which Se status were measured in a number of tumor patients (n = 512). The majority of patients with different tumors (head and neck, lung or rectal cancer, carcinomas of the uterus and prostate cancer, respectively) showed Se concentrations in whole blood that were below the reference range of 110 to 130 μg/L [18]. Interestingly, the tissue Se concentrations were elevated in the carcinoma as compared to the compartment surrounding it. Moreover, also tumor tissues from patients with benign prostatic hyperplasia displayed lower Se concentrations than prostate carcinoma tissue and circulating Se and selenoprotein P concentrations were lower in patients as compared to controls (Table 2) [19,20,21,22,23,24].  These results motivated us to test whether adjuvant Se supplementation may elicit beneficial effects in our tumour patients and provided the scientific rationale for our clinical analytical and intervention studies.

BODY.3. CLINICAL STUDIES ON THE EFFECTS OF SUPPLEMENTAL SE DURING RADIOTHERAPY:
The homeostasis of the human organism is challenged by radio- and chemotherapy and side effects are occurring. A Se-deficient cancer patient may be at specific risk for the unwanted consequences of therapy as usually the nutritional situation in the clinics is sub-optimal and the ongoing disease may impair regular trace element metabolism even further [25]. For these reasons, several studies have been conducted and indicated that supplemental Se elicits some protecting effects on the normal tissue thereby alleviating therapy-induced side effects [26,27,28,29,30,31].  Hence, we initiated the first randomized phase III clinical trials in radiation oncology to test whether adjuvant sodium selenite supplementation improves therapy success and protects normal tissue from damage thereby reducing side effects. The first study was conducted with gynecological patients who received supplemental Se after surgery during radiotherapy. The primary study aims were to verify that adjuvant supplementation successfully increased the Se status in patients and whether this improvement is associated with reduced radiation-induced diarrhea, as this complication constitutes a relevant and frequent side effect in patients treated by pelvic radiotherapy for uterine or cervical cancer. We were able to enroll 81 patients, 39 of them into the Se group (SeG) and 42 into the control group (CG). As expected, both whole blood and plasma Se levels increased in the SeG. Importantly, side effects were less frequent and severe in the SeG and the actuarial incidence of at least CTC 2 diarrhea was significantly reduced in the SeG as compared to the CG. The calculated 10-year overall survival rate of patients in the SeG was 55.3% compared to 42.7% in the CG (p = 0.09). The 10-year disease free survival rate was not different, i.e., a calculated 80.1% in Se-supplemented as compared to 83.2% in the control patients (p = 0.65). There was a tendency that the patients with higher Se status tolerated the radiotherapy better than the ones with relative Se deficiency. Notably, the long-term survival rates were similar between the groups. These observations support the notion that supplemental Se is safe and may indeed elicit some beneficial effects on normal tissue without conferring protection to tumor cells, in clear contrast to what was suspected and assumed by many colleagues [32,33].  A second randomized Se supplementation study in radiation therapy was conducted with patients suffering from head and neck tumors. This study was conducted with 39 patients, of which 22 were enrolled into the SeG and 17 as controls. A significant reduction of dysphagia during the last week of irradiation was observed in response to supplemental Se, especially in the patients with higher plasma and whole blood Se levels (p = 0.04). Similarly, also loss of taste (ageusia) as a typical side effect was observed more frequently in the CG as compared to the SeG, however without reaching statistical significance (p = 0.172) [34].  Collectively, there are scientific experiences with Se in radiotherapy worldwide from at least sixteen clinical studies conducted between 1987 and 2012. From all these study results, it can be concluded that adjuvant Se supplementation tends to improve the general conditions of the patients, their quality of life while at the same time reducing the side effects of radiotherapy. Selenium supplementation did not reduce the effectiveness of radiotherapy and no toxicities were observed under these conditions [35].

BODY.4. DISCUSSION:
The Se status of tumor patients tends to be reduced as compared to control subjects. Adjuvant Se supplementation improves radioprotection of healthy tissue in tumor patients. Nevertheless, our understanding of Se biology in radiation oncology is still very limited and additional clinical studies are needed in order to better appreciate this issue and enable respective adjuvant treatment options. Unfortunately, there are reports claiming that Se supplementation may lead to an increased risk of developing diabetes mellitus. These critical and mainly US-based studies highlighted again the narrow therapeutic width of Se intake in humans and the potential risk associated with Se supplementation of already well-supplied subjects [36,37]. And notably, both studies used Se-rich yeast and pure selenomethionine, respectively and should thus not be extrapolated to short term supplementation with inorganic selenite.  Nevertheless, in view of the marginal Se intake of many Europeans, the majority of patients is likely to benefit from supplemental Se as the potential side-effects have observed in already well-supplied subjects only and not in Se-deficient subjects. Assuming a U-shaped curve of Se status and health effects and in view of the marginal Se supply of Europeans as compared to e.g., US Americans, we conclude that in Europe there is little risk of over-supplementation of cancer patients when using the recommended dosages before and during radiation therapy [18,38,39,40].  Unfortunately, even nowadays there is not yet a general recommendation in favor of or against Se supplementation in cancer patients. Nevertheless, more and more patients treated with curative or palliative radiotherapy in Germany are using adjuvant Se supplementation in a self-motivated and uncontrolled manner. In the future, the practitioner-recommended as well as the self-chosen supplementations with Se need to be better monitored and their effects systematically analyzed. At present, we strongly advocate to take the Se status of tumor patients under oncological therapy and aftercare situation more seriously into account and to consider a respective supplementation before, during or after therapy when the current Se status appears insufficient. To this end, Se status needs to be measured and monitored before, during and after radiation therapy [18].  When we started our research on Se 15 years ago, the oncological community in Germany was very skeptical, since supplemental Se was considered rather toxic than health supporting. 15 years later, a solid data basis exists and some radiation oncologists measure even the Se levels during therapy and compensate in cases of deficiency. But we have to keep in mind that the trace element Se constitutes a small piece only in the bigger puzzle on the parameters affecting therapeutic success in radiation oncology. Still, first convincing results have been achieved and showed that it is worthwhile to conducting further basic and clinical research in this field. The notion that there are no indications that supplemental Se in recommended dosages harms when given to subjects with proven Se deficit provides some confidence into this adjuvant therapy support.

BODY.5. CONCLUSIONS:
Se supplementation has yielded positive and promising results concerning radioprotection in tumor patients. It can thus be considered as a meaningful and promising adjuvant treatment option in subjects with a proven Se deficit. Future clinical studies are needed to better identify those patients who benefit most from supplemental Se, i.e., likely the ones with the lowest baseline Se status. Yet, this hypothesis needs to be tested in sufficiently large intervention studies, in order to better characterize the best supplementation regimen during therapy.

Question: Compared to Control patients what was the result of Supplemental Se on Reduction in radiation-induced diarrhea?
Evidence: side effects were less frequent and severe in the SeG and the actuarial incidence of at least CTC 2 diarrhea was significantly reduced in the SeG as compared to the CG.
Answer: significantly increased