Introduction

Among cancer patients overall, the characteristic clinical picture of anorexia, reduced food intake, weight loss, wasting of both muscle mass and adipose tissue that often precedes death has been named cancer-related anorexia/cachexia syndrome (CACS) [1–4]. Cachexia itself is even the main cause of death in more than 20% of cancer patients [5]. Besides reduced food intake, CACS is due to metabolic abnormalities, with changes not only in energy metabolism, but also in carbohydrate, protein, and lipid biochemistry, and changes in the production by the host immune system of proinflammatory cytokines and circulating tumour-derived catabolic factors, and to increased oxidative stress (OS) [6]. Several cytokines, including IL-1, IL-6, TNF-α, INFα and INF-γ, are involved in the pathogenesis of CACS [7, 8]. The excessive production of proinflammatory cytokines has been implicated, in turn, in the increased OS characteristically found in cancer patients. Increased OS is often marked by an accumulation of free radicals known as reactive oxygen species, such as hydroxyl radicals, superoxide radicals, hydrogen peroxide, and reactive nitrogen species, such as nitric oxide. Recent studies suggest that the association of a chronic inflammatory condition, typical of patients with advanced cancer, with increased OS adversely affects the immune functions [9, 10]. Moreover, besides the abnormalities induced by the tumour itself, a further mechanism causing increased OS is attributable to the use of antineoplastic drugs, particularly alkylating agents and cisplatin, and of radiation therapy [11, 12].

 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. The aim of this study was to verify the effects of the administration of FWGE in a population of patients affected by head and neck cancer, especially in terms of the impact of the use of the product on the multidimensional aspects of their QOL, as assessed according to Spitzer’s index, and on OS.

Patients and methods

A group of 60 patients aged 18–65 years affected by head and neck tumours (stage IIIa, IIIb, IV) were enrolled in the study and divided into two subgroups: group A (control group) or group B. Group A received conventional oncological treatment alone, and group B (FWGE group) were treated with the combination of FWGE and standard antitumoral therapy. All the patients were either able to spontaneously eat or receive enteral nutrition and had life expectancies of at least 3 months. All types of medical, radiochemotherapy and/or surgical treatment of the tumoral illness were maintained in all patients during administration of FWGE . All patients taking part in the study gave written informed consent. The study was conducted following an open-label protocol and included a medical physical examination of the patient at baseline and after 60 days, during which a sample of blood was drawn for routine laboratory tests. For each patient and at each protocol time point the following parameters were recorded: body weight, height, body mass index (BMI), thickness in millimetres of the triceps skinfold, and circulating hydroperoxides (FRAS III test) [22]. 

This last technique involves the photogenic reaction between free radicals in the blood and a chromogenic substance, developing a molecular complex with a maximum peak of absorbance at 505 nm directly correlated with the concentration of the radicals [22]. 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 FWGE 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 Mediterr J Nutr Metab (2008) 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 FWGE in combination with conventional chemotherapy have been described [15].

In our open-label study we examined the effects of the administration of FWGE over a period of 2 months in a group of 22 patients affected by head and neck tumours (stage IIIa, IIIb, IV) receiving conventional chemo- and/or radiotherapy, while a control group of 33 patients with comparable pathology received only conventional antitumoral therapy. In particular, we evaluated the influence of Avemar 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 Avemar 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.