Background and aim Anorexia/cachexia syndrome is frequently correlated with increased oxidative stress (OS). A fermented wheat-germ extract with a standardized benzoquinone content (brand name FWGE) has been shown to exert an intense antioxidant activity with no side effects. The aim of this study was to investigate the effects of FWGE in patients affected by head and neck cancer, correlating the variations with OS with the quality of life as assessed by the Spitzer’s index. Patients and methods A cohort of 60 patients affected by head and neck tumours (stage IIIa, IIIb, IV) were enrolled in the study following an open-label protocol. The patients were assigned to two subgroups, A or B. Group A was treated with conventional oncological therapy alone, and group B was treated with FWGE in addition to standard therapy. After 2 months only 55 patients survived and could be evaluated (29 in the control group and 26 in the FWGE group). Each patient was checked for circulating concentrations of hydroperoxides using the FRAS III test. Results The levels of OS significantly decreased after 2 months in the group receiving FWGE (group). The value of Spitzer’s index was significantly higher in group B, attesting to an improved quality of life. Conclusion Although the specific active substance in FWGE has not yet been identified, the reduction in free oxygen radicals induced by it is correlated with a clinically significant improvement in the quality of life in patients with advanced cancer. 

Indeed, both chemotherapy and radiation therapy are associated with increased production of reactive oxygen species and depletion of critical plasma and tissue antioxidants [6]. An intense antioxidant activity has been shown to be exerted by a fermented wheat-germ extract with a standardized benzoquinone content (code name MSC; brand name FWGE) [14, 15]. This product contains large amounts of chinolonics and flavonoids responsible for an immunomodulatory therapeutic effect, with inhibition of IL-4 and IL-10 production. Moreover, FWGE has recently been shown to induce apoptosis, to inhibit carbon flow to nucleic acid synthesis and to induce the downregulation of major histocompatibility complex (MHC) class I proteins in tumour cells [15–17]. No side effects have been reported with the use of FWGE, which can be considered a medical nutrient [15]. Because of its efficacy and safety, FWGE may play a pivotal supportive role in the treatment of cancer with regard to not only tumour progression, but also attenuating the condition of cachexia associated with terminal malignancy to improve the quality of life (QOL). In fact, cancer and its associated treatment regimens very often result in global disruption of various aspects of QOL, including physical, functional, psychological, and social well-being [18]. Indeed, besides abnormalities in swallowing, chewing and speaking, the treatment can result in permanent disfigurement [19–21]. In all such patients, the use of FWGE could represent a helpful tool to improve the overall nutritional parameters and therefore QOL. 

 Moreover, at each study time point patients filled in the Spitzer’s questionnaire for the evaluation of their QOL [23–25]. The questionnaire includes: activity, daily living, health, support, and outlook. Each field includes three possible statements with scores of 0, 1 or 2, meaning a negative, neutral or positive indications, respectively. The patient must choose the statement that best fits his or her own condition, and the higher the total score, which can range from 0 (minimum) to 10 (maximum), the better the QOL. All patients completed the self-administered QOL questionnaire at the hospital with the help of physicians, once at baseline and again after 2 months. Statistical analysis was performed using Pearson’s test with Yates’ correction for continuity, Student’s t-test and the Mann-Whitney U-test, after checking for the normality of the distributions (by means of the Shapiro-Wilk or Kolmogorov-Smirnov test) and verifying variance homogeneity (by the Levene test). The treatment with Avemar consisted of oral administration of 9 g once a day (or twice a day for patients weighing more than 80 kg), either on an empty stomach or during meals, provided the ingestion of the compound took place at least 2 hours before or at least 2 hours after the intake of products or food containing vitamin C. No negative interactions or undesirable side effects of Avemar in combination with conventional chemotherapy have been described [15]. 

 In particular, we evaluated the influence of FWGE on QOL, assessed according to Spitzer’s index, in relation to variations in the mediators of OS (free oxygen radicals) as detected by the FRAS III test. In fact, a clinically significant OS occurs in patients with advanced cancer [28, 29], and together with CACS, is highly predictive of clinical outcome and survival, besides a more general feeling of well-being. Although the changes in QOL and oxidative status that we observed were related to a relatively short time period, the signs and symptoms of the disease displayed significant variations in terms of the Spitzer’s index and FRAS III test.Besides the presently available oncological treatments, complementary nutritional support with supplements with antioxidant properties, such as vitamins A, C and E, αlipoic acid, N-acetyl cysteine, in combination have been shown to be effective in ameliorating CACS through improved appetite, increased food intake and weight gain, and reduced resting energy expenditure and OS [30]. In this study, we confirmed that treatment with FWGE as an adjuvant to standard oncological therapy results in a greater subjective improvement in well-being than conventional antitumoral therapies alone can achieve in patients with head and neck cancer. The positive influence on mood could act through the free radical scavenging effect of components of FWGE and particularly through their inhibition of proinflammatory cytokines, which have been shown to induce alterations in brain function analogous to the behavioural and biological abnormalities occurring in depressed patients [31]. 

No toxic side effects or disadvantageous interactions with the cytostatic drugs used were recorded. Supportive use of FWGE may thus improve the patient’s performance status and enhance the antitumoral effects of standard therapies. In fact, because of the very short survival of these patients at this stage of the disease, symptomatic advantages in terms of QOL rather than just nutritional aspects should be underlined. Indeed, the results of this study show that administration of FWGE improves QOL and alleviates fatigue even at the relatively short end-point of two months. The biochemical explanation of the effects of FWGE includes protection from OS and modulation of proinflammatory cytokines and enzymes, such as inhibition of ribonucleotide reductase, which is responsible for the conversion of ribonucleotides to the precursors of DNA synthesis deoxyribonucleoside triphosphates, and reduction of cyclooxygenase-1 and -2 activity, which are responsible for the production of inflammation mediators [16, 26]. Moreover, early biochemical events, such as inhibition of tyrosine phosphatase activity and elevation of intracellular Ca2+ influx, induce a significant downregulation of the MHC class I molecules on the surface of the tumour cells, thereby exposing them to the action of natural killer cells [32]. On the other hand, macrophages exposed to FWGE show upregulation of the secretion of TNF-α, resulting in increased antitumour activity of these cells [15]. 

Besides, it has been shown that FWGE is capable of inducing the expression of intercellular adhesion molecule-1 (ICAM-1) on endothelial cells, thereby allowing the development of an effective leucocyte infiltrate of the tumour, an effect that is impaired in human malignancies because of the reduced levels of ICAM-1 in the vasculature of tumoral tissue [33]. However, the specific active substance of FWGE has not yet been identified, and it is not possible, at the moment, to fully elucidate the observed biochemical effects. Thus, a better understanding of the responsible molecule or compound will lead to further development and application of FWGE as a chemopreventive and anticancer drug.