MSC (FWGE ) is a medical nutriment of which preclinical and observational clinical studies suggested an antimetastatic activity with no toxicity. This open-label cohort trial has compared anticancer treatments plus MSC (9 g once daily) vs anticancer treatments alone in colorectal patients, enrolled from three oncosurgical centres; cohort allocation was on the basis of patients’ choice. Sixty-six colorectal cancer patients received MSC supplement for more than 6 months and 104 patients served as controls (anticancer therapies alone): no statistical difference was noted in the time from diagnosis to the last visit between the two groups. End-point analysis revealed that progression-related events were significantly less frequent in the MSC group (new recurrences: 3.0 vs 17.3%, Po0.01; new metastases: 7.6 vs 23.1%, Po0.01; deaths: 12.1 vs 31.7%, Po0.01). Survival analysis showed significant improvements in the MSC group regarding progression-free (P ¼ 0.0184) and overall survivals (P ¼ 0.0278) probabilities. Survival predictors in Cox’s proportional hazards were UICC stage and MSC treatment. Continuous supplementation of anticancer therapies with MSC for more than 6 months is beneficial to patients with colorectal cancer in terms of overall and progression-free survival. 

A fermented wheat germ extract (code name: MSC; brand name: FWGE ), standardised to methoxy-substituted benzoquinones and registered in Hungary in the year 2002 as medical nutriment (reg. no. 503), has recently been shown to induce apoptosis, to inhibit carbon flow to nucleic acid synthesis (Boros et al, 2001; Comı´n-Anduix et al, 2002) and to induce major histocompatibility complex (MHC) class I proteins’ downregulation (Fajka-Boja et al, 2002) in tumour cells. It has also been published that the extract strongly inhibited the development of azoxymethane-induced colon cancer in rats (Zalatnai et al, 2001). In mice experiments, furthermore, the combination of 5-fluorouracil (5FU) injection plus the orally applied MSC was superior to 5FU alone in the inhibition of liver metastases formation of colon cancer origin (Hidve´gi et al, 1999). An open-label, multicentre cohort study was therefore initiated to estimate the expected difference between the progression-free survivals of colorectal cancer patients receiving anticancer treatments alone or anticancer treatments supplemented with MSC. 

 The Regional Helsinki Committees approved the protocol, and all patients gave written informed consent before entering into the study The two cohorts of patients (MSC and ‘control’) were formed according to the patients’ preference, since MSC was freely available as an over-the-counter product. Patients were asked if they prefer to take MSC, and thus enrolled in the MSC cohort. Those patients who refused to take the preparation formed the control cohort. The decision of treatment group assignment according to patients’ preference was carried out on ethical basis, that is, those patients who otherwise would take MSC, got it free, and those who otherwise would not wish to take, served as control. By this procedure, no direct randomisation or stratification was performed. At the time of check-ups, control patients were always routinely asked if they take any dietary supplement or medical nutriment including MSC and, randomly chosen sera of these patients were analysed for 2-methoxy-benzoquinone (MBQ) and 2,6-dimethoxy-benzoquinone (DMBQ) contents, which are specific indicators of MSC administration. Patients answering ‘yes’ to the question of taking MSC, or having benzoquinone-positive sera, were excluded from the control cohort. The measurement of absorption of methoxy-substituted benzoquinones (MBQ and DMBQ), whose markers were in the form of glycosides in crude wheat germ, and were liberated as aglycones by the process of fermentation, served as a specific monitoring technique of MSC administration, and thus also of compliance. Sample preparation was carried out by solid-phase extraction of the sera, followed by reversed-phase high-performance liquid chromatography. Markers MBQ and DMBQ were detected by mass spectrometry using singleion recording. 

The compounds were analysed by atmospheric pressure chemical ionisation. The detection limit was 2 ng per 10 ml serum. Besides this analytical monitoring, patients of the MSC cohort had to account for the empty containers of the nutriment before having received the new supply. The survival analysis was chosen with power 1–b ¼ 0.8 ¼ 80% and with a significance level a ¼ 0.05 ¼ 5%; for these options, using the Freedman’s procedure, the minimal required sample size was 62 patients per group, assuming a disease-free survival probability in the control group to be roughly equal to 50% at average followup, and an estimated disease-free probability increased by 25% in the MSC group, as deducible from previous animal studies, as well as from early clinical experiences. Beyond the anticancer therapy for the group of patients of the MSC cohort, 9 g of MSC, dissolved in 150 ml of water, were taken orally once daily uninterruptedly and continuously throughout the study but, at least for more than 6 months. The treatment time was measured as the interval between the first and the last visits completed. Patients of the control cohort received the anticancer treatments alone. The term ‘anticancer treatments’ stands for the 5-FU-based standard Mayo Clinic chemotherapy regimen and/or radiation therapy following surgery. All patients were evaluated at baseline, at the end of the first month, and every 12 weeks afterwards.

 Evaluation included assessment of all measurable lesions by imaging (radiographic, ultrasonic or magnetic resonance) techniques, laboratory tests (haematology, chemistry and urinalysis), physical examination and data collection of treatment-related toxicities. Tumour progression was defined as an increase of at least 25% in the overall area of the tumour size or the appearance of any new lesions. Deaths were also reckoned in progression. Time-related events were measured from the date of diagnosis. The primary end point of this study was to compare progression-free survivals of the two cohorts. For this case, the two-tailed, unstratified log-rank test (Kaplan –Meier method), where Po0.05 indicates statistical significance, was used. For other comparisons, the z-test, Mann–Whitney’s z-test, Fisher’s exact test and Student’s t-test were applied. For the analysis of the effects of different variables (age, sex, disease staging, chemotherapy, radiotherapy, MSC administration) on survival, Cox’s proportional hazards (PH) model was used. The Cox PH assumptions for this analysis have been evaluated for the six independent variables taken into account (see also Table 3) by using the Schoenfeld residuals (Schoenfeld, 1982) of the general form for each covariate xu, such that ruj is the difference between the covariate value for the failed jth observation and the average of the covariate values, weighted on the basis of estimated hazard from the Cox model; the residual analysis carried out by means of the generalised method, developed by Grambsch and Therneau (1994), has shown no evidence of violations of Cox’s PH assumptions.

There was also no significant difference between the two cohorts in the number of patients receiving chemotherapy (z ¼ 1.819; P ¼ 0.069). However, significantly more patients of the control cohort had received radiotherapy (z ¼ 3.406; Po0.001). Except for mean age at entry, at baseline the prognoses of the MSC patients were significantly poorer than those of the control patients. At end-point analysis, progression-related events (new recurrent disease, new metastatic lesions, deaths) were significantly more frequent in the control cohort (Table 2). Log-rank analyses (Kaplan– Meier estimates) also showed significant differences in favour of the MSC patients in the cumulative probabilities of both progression-free and overall survivals (Figures 1 and 2). Strong predictors of survival in a Cox’s proportional hazards model (variable follow-up) were UICC stage and MSC treatment only (Table 3). The administration of the medical nutriment was safe. No serious adverse event (NCI-CTC Grades 3–4) was observed. Generally, the greatest disadvantage of this preparation came from its rather unpleasant taste, but no violation of the compliance was detected, and according to blood analyses, no variation in the degree of absorption of MSC by the patients was found. With respect to the MSC cohort, the following side effects of MSC (with the absolute number of cases) were reported: diarrhoea (four), nausea and vomiting (two), flatulence (one), repletion (one), soft stool (one), constipation (one).

 It is interesting that similar to its 70% neoplastic tumour-preventing effect in an experimental colon carcinogenesis model (Zalatnai et al, 2001), in the present study MSC decreased the risk of death among colorectal cancer patients by nearly 70%. (see the exp(b) values listed in Table 3, calculating the following: 100  (1– 0.33) ¼ 0.67 ¼ 67%). Besides these observed benefits of supplemental MSC in human colorectal cancer, it has recently been shown in a randomised trial that this extract is also beneficial concerning disease progression in stage III melanoma patients (Demidov et al, 2002). It has also been reported that MSC supplementation improves quality of life and alleviates fatigue in advanced lung cancer (Hidve´gi et al, 2003). MSC displays multiple effects on the immune system. The downregulation of MHC class I molecules on the membrane surface of the tumour cells by MSC increases the natural killer cell activity against neoplastic cells (Fajka-Boja et al, 2002). The upregulation of tumour necrosis factor alpha (TNF-a) secretion by the MSC-treated macrophages increases the antitumour activity of these cells (Telekes and Hidve´gi, 2001). It is noteworthy that MSC enhances the activity of two of the most effective anticancer cellular immune mechanisms. It has also been shown that MSC upregulates the expression of intercellular adhesion molecule-1 (ICAM-1) on the endothelial cells (Telekes and Hidve´gi, 2001). 

It is known that endothelial cells of the vasculature of human solid tumours have a decreased expression of ICAM-1 compared to normal endothelial cells’ tissue, and this phenomenon can be considered as a tumour-derived escape mechanism since the development of an efficient leukcocyte infiltrate of the tumour is impaired (Griffioen et al, 1996). MSC not only induced the production of ICAM-1 but also showed synergy with the similar effect of TNF-a. These observations may, at least partly, explain the antimetastatic effect of MSC. It has also been demonstrated that MSC induces apoptosis of cancer cells (Fajka-Boja et al, 2002). A recent study of the underlying mechanism behind the programmed cell death induction effect of MSC has pointed to the involvement of poly(ADPribose) polymerase cleavage and thus to the role of caspase-3, which indicated that decreasing cell motility and therefore inhibition of metastasis could also be direct consequences of MSC treatment (Comı´n-Anduix et al, 2002). A further plausible hypothesis on the mechanism behind these positive clinical findings might come from an experiment in which MSC also showed significant therapeutic benefit in naive mice with lupus (SLE). The extract ameliorated the disease, downregulated the autoantibody production and increased Th1- and delayed Th2 responses (Ehrenfeld et al, 2001). The shifting of the Th1/Th2 balance towards an increased cellular immune response might have positive consequences in the mentioned human cancers.