Impact of treatment planning target volumen (PTV) size on radiation induced diarrhoea following selenium supplementation in gynecologic radiation oncology - a subgroup analysis of a multicenter, phase III trial

The essential trace element selenium (Se) is needed during the biosynthesis of a number of selenocysteine (Sec)-containing selenoproteins. Se supply by the daily nutrition varies considerably between populations, being replete in large areas of the US and rather deficient or sub-optimal in many areas of central Africa, Asia and whole Europe. Among the functionally characterized selenoproteins are a number of enzymes crucially involved in the central antioxidative systems of the human body, namely the glutathione peroxidase (GPx) and the thioredoxin reductase (TRR) isoenzymes. In a number of epidemiologic analyses, Se deficiency has been associated with increased infection risk and adverse mood states. Se has been shown to possess cancer-preventive and cytoprotective activities in both animal models and humans. It is well established that Se has a key role in redox regulation and antioxidant function, and hence in membrane integrity, energy metabolism and protection against DNA damage. These and other functions are mediated through a small number of selenoproteins encoded by 25 separate human genes [1‐4].

Radio- and chemotherapy, disease-dependent alterations of metabolism as well as the suboptimal nutrition of cancer patients in the clinics might aggravate the situation in a Se-deficient patient even further, and increase the likelihood of clinically relevant Se deficiency and radiation-induced side effects [5‐7].

Preliminary clinical evidence indicates that Se functions as a radio- and chemoprotector with the ability to alleviate side effects of tumour specific chemotherapy or radiotherapy treatments [8‐11].

In 2003, an English retrospective study indicated a positive correlation between initial serum Se levels and the dose delivery of chemotherapy and outcome in patients with aggressive non-Hodgkin´s lymphoma. In light of the results, the authors hypothesized that specific selenocompounds including methylseleninic acid and selenodiglutathione were involved in inducing preferential cell death in lymphoma cell lines and primary lymphoma cultures, which may be partly attributable to an increased generation of reactive oxygen species [12, 13].

The German Working Group Trace Elements and Electrolytes in Oncology (AKTE) conducted the worldwide sole randomized phase III clinical studies to examine the radioprotective properties of sodium selenite in radiation oncology. The first of these randomized trials enrolled head and neck tumour patients undergoing radiation therapy [14]. A total of 39 patients were randomized into two groups. 22 were enrolled in the selenium group (SeG) and 17 in the control group (CG). Weekly analyses were performed and a significant reduction of dysphagia in the SeG at the last week of irradiation (p=0.04) was observed. This small randomized trial had shown some limited effects of Se in the prevention of ageusia (loss of taste) and dysphagia due to radiotherapy because of head and neck cancer. Most likely due to the small number of patients included a clinical relevant radioprotection was not observed [14].

In contrast to these data the second randomized phase III study in postoperative gynecological patients with supplementation of Se under radiotherapy conditions supported the findings of Last et al. [12]; especially the patients with higher plasma and whole blood Se levels tolerated the side effects of radiotherapy significantly better without any obvious impairment of survival data. The main result of this study showed a significant benefit of sodium selenite supplementation with regard to Se deficiency and RT-induced diarrhoea in patients with cervical and uterine cancer [15].

Aim of this study was to perform a subgroup analysis of the data available from the initial study [15]. Specifically, we wanted to examine whether there is a relation between the PTV size and the Se effect concerning radiation induced diarrhoea.

Our study analyzes the effects of Se supplementation in a group of patients with initially low Se status after surgery during RT treatment depending on PTV-size of radiation therapy. Se supplementation improved the Se status of our patients under the therapy conditions, and yielded a significant reduction of diarrhoea as published recently [15]. The increased biosynthesis and hence activities of the different GPx and TRR isoenzymes might have been responsible for these effects by an enhanced neutralization of radiation-induced hydroperoxides and free radicals in the small intestinal mucosa included in the irradiation volume [5, 17]. Beside the antioxidative capacity in the healthy tissue a selective unusual activation of wild-type p53 by Se-dependent reduction of two critical cysteine residues by redox factor 1 (Ref 1) might have contributed to the consecutive activation of DNA-repair in healthy cells of the small intestinal mucosa [18‐21]. Furthermore, an increased biosynthesis of selenoprotein P, which is responsible for Se homeostasis, transport of selenium to tissues, antioxidant activities and decrease of lipid hydroperoxides, might have further provided some protection to the healthy cells in the irradiated tissue [22]. In addition, Se may have reduced translocation of the inflammatory transcription factor NFkB into the nucleus and thereby diminished cytokine production and release [23‐25]. Finally, Se might have stimulated the regulatory mechanisms of repopulation into the small intestinal mucosa included in the irradiation volume at a time before they were activated by irradiation [26].

Here, we provide results indicating that the radioprotective effect of Se concerning radiation induced diarrhoea achieved significance primarily in patients with PTV > 1302 ml. Thus, it can be speculated that in correlation to a growing PTV a threshold concerning the number of radiation induced free radicals exists. As a consequence, it is conceivable that in patients with PTV <=1302 ml the endogenous detoxification system works sufficiently without the help of supplemental Se. In comparison, in cases with PTV >1302 ml and consecutively expected higher count of radiation induced free radicals we observed that Se supplementation yielded a significant prevention of diarrhoea. This finding may be due to a higher demand for Se-dependent protective enzymes and an exhaustion of the Se reserve in the tumour patients if not efficiently supplemented during RT.

Unfortunately, in 2011 there is still no general recommendation in favour of or against Se supplementation for alleviating the side effects of chemotherapy, radiotherapy and surgery in cancer patients [27]. Nevertheless, our results support the published findings of Last et al. [12] and highlight that in patients with higher blood selenium levels the tolerance of radiotherapy was significantly better. Therefore, we strongly advocate to take the Se status of the tumour patients under therapy more seriously into account and to consider a respective supplementation prior to therapy when the current Se status appears to be insufficient [28, 29].

Se supplementation during RT of the pelvic region is effective to improve blood Se status in Se-deficient cervical and uterine cancer patients, and reduces episodes and severity of RT-induced diarrhoea. This effect was most pronounced and significant in patients with large PTV (> 1302 ml).