EXECUTIVE SUMMARY Introduction Separated wheat germ is traditionally included in healthy foods, consumed or served as raw material for extracts rich in vitamin E. During the 1990s, a new, fermented wheat germ extract for human consumption was invented by Professor Máté Hidvégi in Hungary. The standardized manufacturing technology included the extraction of wheat germ, the fermentation of the extract, followed by separation of the fermentation liquid, microencapsulation, drying, and granulation. The resulting powder was named FWGE pulvis (or simply FWGE ), and the granulate is also known as FWGE . For a 70-kg weight adult, the single daily dosage of FWGE contains 8.5 g of FWGE pulvis plus flavoring ingredients, such as fructose and arome. After being dissolved in 150 ml of cold water, FWGE should be drunk preferably before a meal. The product has been approved as a dietary food for special medical purposes in cancer patients by the National Institute of Food Safety and Nutrition of Hungary. This review was requested by the Senior Director of the Food Safety and Quality Division, Ministry of Health Malaysia following a request to import FWGE granulate as a special purpose food for cancer patients. Objective/aim To assess the effectiveness, safety and cost-effectiveness of FWGE granulate as a dietary food / special purpose food for cancer.

EXECUTIVE SUMMARY Introduction Separated wheat germ is traditionally included in healthy foods, consumed or served as raw material for extracts rich in vitamin E. During the 1990s, a new, fermented wheat germ extract for human consumption was invented by Professor Máté Hidvégi in Hungary. The standardized manufacturing technology included the extraction of wheat germ, the fermentation of the extract, followed by separation of the fermentation liquid, microencapsulation, drying, and granulation. The resulting powder was named FWGE pulvis (or simply FWGE ), and the granulate is also known as FWGE . For a 70-kg weight adult, the single daily dosage of FWGE contains 8.5 g of FWGE pulvis plus flavoring ingredients, such as fructose and arome. After being dissolved in 150 ml of cold water, FWGE should be drunk preferably before a meal. The product has been approved as a dietary food for special medical purposes in cancer patients by the National Institute of Food Safety and Nutrition of Hungary. This review was requested by the Senior Director of the Food Safety and Quality Division, Ministry of Health Malaysia following a request to import FWGE granulate as a special purpose food for cancer patients. Objective/aim To assess the effectiveness, safety and cost-effectiveness of FWGE granulate as a dietary food / special purpose food for cancer.

 Results and conclusions Benefits to patients with colorectal cancer, head and neck cancer as well as post surgical cancer patients cannot be determined as the evidence are limited and of poor quality of evidence. Hence, further research into the role of FWGE as a dietary food / special purpose food in these areas is warranted. Methods Five articles were included that consists of five non-randomised clinical trials and comparative studies. Literatures were searched through electronic databases specifically PubMed/Medline, Cochrane, OVID, INAHTA and also in general databases. Google was used to search as additional web-based information. In addition websites for existing HTA agency, society websites and cross-referencing of the articles retrieved were also carried out accordingly to the topic. A critical appraisal of the retrieved papers was performed and the evidence level was graded according to the US/Canadian Preventive Services Task Force. 1 FWGE Granulate as Dietary Food / Special Purpose Food for Cancer 1. 

INTRODUCTION Wheat germ, if left in flour, has an adverse effect on the functional properties of dough and therefore on breadmaking quality. Therefore, most wheat germ is milled as part of mill feed, and a smaller portion is separated during the milling process. Separated wheat germ is traditionally included in healthy foods, consumed or served as raw material for extracts rich in vitamin E.1 During the 1990s, a new, fermented wheat germ extract for human consumption was invented by Professor Máté Hidvégi in Hungary.2 The standardized manufacturing technology included the extraction of wheat germ, the fermentation of the extract, followed by separation of the fermentation liquid, microencapsulation, drying, and granulation. The resulting powder was named FWGE pulvis (or simply FWGE ), and the granulate is also known as FWGE .1-2 For a 70-kg weight adult, the single daily dosage of FWGE contains 8.5 g of FWGE pulvis plus flavoring ingredients, such as fructose and arome. After being dissolved in 150 ml of cold water, FWGE should be drunk preferably before a meal. The product has been approved as a dietary food for special medical purposes in cancer patients by the National Institute of Food Safety and Nutrition of Hungary. 

MEDLINE(R) In-process and other Non-Indexed Citations and Ovid MEDLINE(R) 1948 to present 2 EBM Reviews - Cochrane Central Register of Controlled Trials-until 3 rd Quarter 2013 EBM Reviews – Database of Abstracts of Review of Effects until 3rd Quarter 2013 EBM Reviews - Cochrane database of systematic reviews - 2005 to 2013 EBM Reviews - Health Technology Assessment – until 3 rd Quarter 2013 NHS economic evaluation database – until 3 rd Quarter 2013 Other databases (example); PubMed Horizon Scanning database (National Horizon Scanning Centre, Australia and New Zealand Horizon Scanning Network, National Horizon Scanning Birmingham) FDA website INAHTA MHRA Google scholar was used to search for additional web-based materials and information. Appendix 1 showed the detailed search strategies.  Last search was conducted on 19th August 2013. 4.2. Selection A reviewer screened the titles and abstracts against the inclusion and exclusion criteria and then evaluated the selected full-text articles for final article selection. Relevant articles were critically appraised using Critical Appraisal Skills Programme (CASP) and evidence graded according to the US / Canadian Preventive Services Task Force (Appendix 2). Data was extracted and summarised in evidence table (see Appendix 3). 

5. RESULTS AND DISCUSSION The search strategy yielded a total of 215 relevant titles and 111 abstracts were screened using the inclusion and exclusion criteria. After screening, 82 abstracts were found to be irrelevant. In total five full text articles which met the inclusion/exclusion criteria and quality of studies were included in this systematic review. 5. 1. EEFICACY/ EFFECTIVENESS Five articles were included that consists of five non-randomised clinical trials and comparative studies. Jakab F and Mayer A et al in 2007 reported a Phase II clinical trial to see whether FWGE adds any therapeutic benefit to surgery or chemothery in colorectal cancer. From 1998 to 1999, eighteen control and twelve consecutive colorectal patients were enrolled at the Uzsoki Teaching Hospital, Budapest.6 All patients underwent curative surgery. The control patients received no other therapy or adjuvant chemotherapy alone. The other group was given either 9 gm FWGE mar alone or FWGE plus adjuvant chemotherapy. The median follow up was nine months. No new metastases developed in the FWGE group while on the contrary several new metastases developed in the control group. Jakab F and Shoenfeld Y et al in 2003 reported an open-label comparative study of colorectal cancer patients from three oncosurgical institutions at Uzsoki Teaching Hospital of Budapest, University of Szeged and University of Debrecen, Hungary to estimate the expected difference between the progression- free survivals of colorectal cancer patients receiving anticancer treatments alone or anticancer treatments supplemented with FWGE .

7 Sixty-six colorectal cancer patients received FWGE supplement for more than six 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. Time-related events were measured from the date of diagnosis. End-point analysis revealed that progression-related events were significantly less frequent in the FWGE group o (new recurrences: 3.0% in FWGE group versus 17.3% in control group, P<0.01; o new metastases: 7.6% in FWGE group versus 23.1% in control group, P<0.01; o Deaths: 12.1% in FWGE group versus 31.7% in control group, P<0.01). Survival analysis showed significant improvements in the FWGE group regarding progression-free (P=0.0184) and overall survivals (P=0.0278) probabilities. Strong predictors of survival in a Cox’s proportional hazards model (variable follow-up) were UICC stage (Union for International Cancer Control staging) and FWGE treatment only. The study was short termed; however, the authors suggested that continuous supplementation of anticancer therapies with FWGE for more than 6 months may have 4 potential benefits to patients with colorectal cancer. Further clinical studies are needed to confirm this. A group of sixty patients aged 18–65 years affected by head and neck tumours (stage IIIa, IIIb, IV) were enrolled in a study by Sukkar SG et al in Italy.8 Patients were 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 antitumor therapy. All the patients were either able to spontaneously eat or receive enteral nutrition and had life expectancies of at least three months. 

The study was conducted following an open-label protocol and included a medical physical examination of the patient at baseline and after sixty days. At each study time point patients filled in the Spitzer’s questionnaire for the evaluation of their QOL. After two months only fifty-five patients survived and could be evaluated (twenty nine in the control group and twenty six in the FWGE group). Each patient was checked for circulating concentrations of hydroperoxides using the FRAS III test. The results showed that: The levels of oxidative stress (OS) significantly decreased after two 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. The study was short termed, however, it was suggested by the authors that treatment with FWGE as an adjuvant to standard oncological therapy may result in a greater subjective improvement in well-being of the patients than conventional antitumor therapies alone. Further clinical studies are needed to confirm this. An open-label, randomized, pilot, phase II clinical trial was conducted by Demidov LV et al to assess the supportive value of FWGE in the postsurgical adjuvant setting, at the N. N. Blokhin Cancer Research Center in Moscow between 2000 and 2001.9 Postoperative patients were randomized to either dacarbazine (DTIC) plus FWGE (twenty six patients) or to dacarbazine (DTIC) alone (control- twenty six patients).

 Although the administration of FWGE lasted for twelve months to test if this dietary food had any effect on progression free survival, post study patients were followed up for about an additional 7- year period. At the end of the 7-year-long follow-up period: Log-rank analyses (Kaplan-Meier estimates) showed significant differences in both progression-free (PFS) and overall survival (OS) in favor of the FWGE group. Mean PFS: 55.8 months (FWGE group) versus 29.9 months (control group), p=0.0137. Mean overall survival: 66.2 months (FWGE group) versus 44.7 months (control group), p = 0.0298. An open-label, matched-pair (by diagnosis, stage of disease, age, and gender) pilot clinical trial was conducted by Garami M et al to compare the results between the combined administration of the medical nutriment FWGE with cytotoxic drugs (intervention group) and the continued administration of standard anticancer drug (control group) to reduce the incidence of treatment-related febrile neutropenia in children with solid cancers. 10 Twenty-two randomly chosen patients (11 pairs) with histologically proven different pediatric malignant solid tumors were enrolled in this study between December 1998 and May 2002. 

All of them had been treated at the Oncology Unit of the Second Department of Pediatrics at the Semmelweis University in Budapest. The results were as follows: 5 During the treatment (follow-up) period, there was no recognizable progression of the malignant disease, whereas at end-point (Dec. 31, 2003), the number and frequency of febrile neutropenic events (the latter expressed as percentages of the total number of chemotherapy cycles) significantly differed between the two groups: 30 febrile neutropenic episodes (24.8%) in the FWGE group versus 46 (43.4%) in the control group (Wilcoxon signed rank test: z = 2.090; P = 0.037) The study was short termed; however, the authors suggested that the continuous supplementation of FWGE may help to reduce the incidence of treatment-related febrile neutropenia in children with solid cancers. Further clinical studies are needed to confirm this. 5.2 SAFETY There was no retrievable scientific evidence on the adverse events of FWGE granulate. 5.3 COST/COST-EFFECTIVENESS There was no retrievable scientific evidence on the cost-effectiveness of FWGE granulate. 5.4 LIMITATIONS Our study has several limitations. The selection of the studies and appraisal was done by one reviewer. Although there was no restriction in language during the search, only English full text articles were included in the report.