Arabinoxylan Rice Bran (MGN-3/Biobran) for the Treatment of Hepatocellular Carcinoma and Hepatitis B and C Infection
Condition: Hepatocellular Carcinoma; Hepatitis B
MeSH terms: Hepatitis A; Hepatitis B; Carcinoma; Carcinoma, Hepatocellular; Hepatitis
Study type: Interventional

Summary: 
      Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide with an estimated
      626,000 new cases per year worldwide, accounting for 5.7% of new cancer cases. Although
      resection and transplantation offer the best 5-year survival rates, not all patients are
      suitable surgery candidates. Other treatments include pericutaneous ethanol injection (PEI),
      radiofrequency ablation (RFA), and transarterial oily chemoembolization (TOCE), all of which
      enhance the survival rate and aid in shrinkage of the tumor. The very low survival rate among
      HCC patients, 3-5%, reflects the inadequacy of conventional therapies for the disease and
      highlights the necessity of finding new treatments or modifying the current treatment.

      The hepatitis B virus (HBV) causes liver disease that can range in severity from a mild
      illness that lasts several weeks (acute hepatitis B) to a long-term chronic illness. An
      estimated 2 billion people have been infected with HBV worldwide, resulting in more than 350
      million individuals with chronic, long-term liver infections. Patients with chronic HBV
      infection are at a great risk for the development of cirrhosis, hepatic failure, and HCC.
      There is no cure for hepatitis B and care is mostly palliative. There are several anti-viral
      and interferon drugs, such as Entecavir and Interferon α therapy, which can help some
      patients. However, these drugs are costly, thousands of dollars per year, and are not widely
      available in many countries, especially in the developing world. Vaccination is available and
      effective and is recommended for all individuals at risk for HBV infection. However,
      vaccination is only effective in individuals who have not been exposed to HBV. Hepatitis B is
      closely linked to liver cancer, which is almost always fatal.

      MGN-3/Biobran is an arabinoxylan extracted from rice bran that is treated enzymatically with
      an extract from Shiitake mushrooms. MGN-3 demonstrated anti-cancer activity in vivo in mice
      and humans. The present study was carried out to examine whether combining the current
      conventional treatment with a food supplement, arabinoxylan rice bran (MGN-3/Biobran), may
      improve the outcome of the disease and increase the survival rate of patients with HCC or
      HBV. We hypothesize that a combinatory treatment of conventional therapy with MGN-3/Biobran
      will augment the therapeutic effect seen when patients are treated with conventional therapy
      alone.
    

Detailed description: 
      Objective(s): The objective of this study is to analyze a data from a study that examined the
      biotherapeutic effect of combining conventional therapy in the presence of MGN-3/Biobran. The
      study focused on treatment of patients in Vietnam with hepatocellular carcinoma (HCC) and
      Hepatitis B and C.

      Purpose of the study:

      Aim 1: The biotherapeutic effect of combining conventional therapy and a natural, non-toxic
      arabinoxylan rice bran (MGN-3/Biobran) for the treatment of patients with HCC will be
      examined. Parameters under investigation include, lifespan of the patient, progression of the
      disease (tumor size), and recurrence of the disease.

      Aim 2: The biotherapeutic effect of combining conventional therapy and a natural, non-toxic
      arabinoxylan rice bran (MGN-3/Biobran) for the treatment of patients with Hepatitis B virus
      (HBV) will be examined. Parameters under investigation include alanine transaminase (ALT)
      levels, HBV antigen levels, and HBV DNA levels.

      Methodology:

      Study Design:

      Secondary analysis of data from "The effects of Biobran/Lentin Plus in the adjuvant therapy
      of hepatocellular carcinoma and chronic hepatitis B" study. The study was a randomized
      controlled design that was conducted from 6/2006 to 7/2008 at the 108 Military Central
      Hospital, Hanoi, Vietnam with Dr. Mai Hong Bang as the Principal Investigator. MGN-3/Biobran
      was approved by Vietnam Ministry of Health with import VISA No.12577/2005/CBCL-YT. Therefore,
      The 108 Military Central Hospital approved the study for treatment of patients with HCC and
      hepatitis B too.

        1. Hepatocellular Carcinoma (HCC): Sixty-eight patients of both sexes, male and female,
           with HCC were divided into two groups: group 1 (38 patients) was treated with
           conventional therapy plus MGN-3 for 3 years, and group 2 (30 patients) was treated with
           conventional therapy alone. At various intervals and at the end of the study patients
           were assessed for the following: lifespan of the patient, progression of the disease
           (tumor size), and recurrence of the disease.

        2. Hepatitis B virus (HBV): Sixty-two patients of both sexes, male and female, with HBV
           were divided into two groups: group 1 (32 patients) was treated with conventional
           therapy plus MGN-3 for 3 years, and group 2 (30 patients) was treated with conventional
           therapy alone. Conventional therapy given was the anti-viral drug, Entecavir.

           Data were collected every six months for two years. Parameters under investigation
           included: alanine transaminase (ALT) levels, HBV antigen (HeBAg), and HBV DNA levels.

           Patients were treated with standard treatment (transarterial oily chemoembolization
           (TOCE) for HCC; Entecavir for HBV) in combination with the experimental treatment,
           arabinoxylan rice bran (MGN-3/Biobran) and compared with a control group given standard
           treatment alone. Standard treatment was administered for 3 years. The experimental
           treatment (MGN-3/Biobran) was administered at a dose of 1g/day for 3 years.

           Patient characteristics and measures:

             -  Group: two groups Group1 = Conventional therapy Group2 = Conventional therapy +
                MGN-3

             -  Age range of the patients: 30-68 years old

             -  Gender: male and female

             -  Medical condition(s):

           Hepatitis infection:

           Hepatitis B: HCC HBV Hepatitis C: HCC Hepatitis B and C: HCC

             -  Number of tumors/patient (HCC study)

             -  Tumor size (HCC study): was measured in cm. <3 cm 3-6cm >6cm

             -  AFP level: HCC - ≤500 ng/ml >500 ng/ml

             -  HBV viral load

             -  ALT level: HCC

             -  HBV <100 IU/ml 100-250 IU/ml: 37 patients >250 IU/ml: 15 patients

             -  Tumor Recurrence

             -  Patient Survival

           Intervention details Treatment group(s): HCC - Intervention only (PEIT, TOCE, PEIT +
           TOCE, TOCE + RFA) Intervention + MGN-3 HBV - Intervention only (Entecavir) Intervention
           + MGN-3 Control(s): Intervention only group served as a control Co-interventions:
           Intervention + MGN-3 group Duration of intervention: HCC - 3 years HBV - 2 years

           Who delivered intervention? Dr. Mai Hong Bang and some other doctors. A consultation
           before delivering intervention for all patients

           Outcome measures HCC: ALT level, AFP level, tumor size, patient survival, recurrence
           HBV: ALT level, HBV DNA level, recurrence, patient survival, HBeAg seroconversion

           Methods of assessing outcome measures:

           ALT and AFP levels, HBV DNA level, HBeAg seroconversion: blood test Tumor size:
           ultrasonography and radiography Patient survival: observation

           When were they measured? Every 6 months Length of follow-up: HCC - 3 years HBV - 2 years

           Inclusion criteria:

           HCC patient Criteria of inclusion - Patient had ≤3 tumors (1 tumor under 12cm/ or 2
           tumor under 5cm /or 3 tumor under 3cm) - Stage of disease: Okuda I,II and Child Pugh A,B

             -  Liver biopsy: HCC positive

             -  General condition: average/ good

           Chronic hepatitis B patient Criteria of inclusion

           - Patient have been carrying HBsAg over 6 months

           - ALT was over or equal 2 times ULN

             -  HBV-DNA level: 104 (log10 copies/ml) with HBeAg(-) patient and 105 (log10
                copies/ml) with HBeAg(+) patient

           Exclusion criteria:

           HCC patient Criteria of exclusion - Tumor size is too big (over 12 cm), multiple tumors
           (over 3 tumors or diffuse tumor type) - Prothrombin under 60%

           - Severe liver or/ and renal insufficiency

             -  Portal vein body thrombosis

           Chronic hepatitis B patient Criteria of exclusion

             -  Used immunotherapy or corticotherapy for 6 months

             -  Pregnant woman

           Procedures: Upon approval by IRB, the data will be analyzed using statistical analysis
           and the data will be published in a peer-reviewed journal, as this data has not yet been
           published. We will receive the data from the PI (Dr. Mai Hong Bang, MD Ph.D., Associate
           Professor, Department of Hepatogastroenterology). After receiving the IRB approval, we
           will conduct secondary analysis of the data. We will receive the data as an electronic
           file excel file format with the code book for all the variables. We will do frequency
           and data checking and data management to prepare the data for analysis. We will do
           recoding and create new variables from the existed variables as a way to prepare for the
           data analysis.

           Benefits to subjects: Conventional therapies for HCC and HBV, in addition to their
           toxicity, do not substantially improve the survival rate of the patients. The
           combination of MGN-3/Biobran with these conventional therapies may improve the survival
           rate of the patients and decrease the rate of recurrence.

           Benefits to the Community: There is a disproportionately high incidence of HCC in
           developing countries, and over 50% of HCC cases occur in Asia. Hepatitis B is closely
           linked to liver cancer, which is almost always fatal. It is estimated that nearly 80% of
           all liver cancer worldwide is caused by hepatitis B infection. Therefore, there is a
           need for new treatments with minimal to no side effects to combat these diseases. This
           study will determine the potential of MGN-3/Biobran combined with conventional therapy
           to improve the outcome of these diseases.
    

Intervention name(s): PEIT; TOCE; TOCE plus PEIT; TOCE plus RFA; MGN-3; Entecavir
Intervention type(s): Procedure; Procedure; Procedure; Procedure; Dietary Supplement; Drug
Intervention description(s): For patients with HCC: Ethanol (99.5%) 3-15 ml/treatment(mean 8ml/treatment) , 2 times/week (mean 6 treatment/patient). For patients with a tumor size under 5 cm in diameter, we applied the formula of M. Ebara: V = 4/3∏ (r+0.5)3 (V: total Ethanol volume, r: radius of tumor).
Precise treatment was dependent on tumor size, outcomes after first PEIT treatment and time to recurrence of disease.; For patients with HCC: Adriamycine was mixed with lipiodol, Adriamycine 20-60mg/treatment (mean 40mg/treatment),lipiodol 5-20ml/treatment(mean 12ml/treatment), 1-2 months between treatments, 2-5 treatments/patient (mean 3 times/patient), which depended on tumor size, outcomes after first TOCE and time to recurrence of disease.; A combination of transarterial oily chemoembolization and pericutaneous ethanol injection therapy are given for patients with HCC.; For patients with HCC: A combination of transarterial oily chemoembolization plus radiofrequency ablation is given. For RFA: On mission 60w/s , 5minutes/circle, 2-4 circles/treatment, 1-2 treatments/week (tumor size under 2cm: 1 treatment; 2-4 cm: 2-3 treatments,over 4 cm: 3-5 treatments); For patients with HCC or hepatitis B, arabinoxylan rice bran food supplement is given. 1 gram per day, every day, for a duration of 12 months. For the MGN-3 group, the interventional therapy was given with MGN-3 simultaneously.; For patients with hepatitis B viral infection, a dose of 0.5mg/day, every day, was given for a duration of 24 months.
Other intervention name(s): Pericutaneous Ethanol Injection Therapy; Pericutaneous Ethanol Injection; PEI; Transarterial oily chemoembolization; Transarterial oily chemoembolization; Pericutaneous ethanol injection therapy; Pericutaneous ethanol injection; Transarterial oily chemoembolization; Radiofrequency ablation; Peak Immune 4; BioBran; Lentin Plus 1000; Baraclude
Intervention MeSH terms: Ethanol; Entecavir
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: HCC; HBV; MGN-3; BioBran; Alternative Therapy