Effects of drinking hydrogen-rich water on the quality of life of patients treated with radiotherapy for liver tumors

  • Ki-Mun Kang1,

    Affiliated with

    • Young-Nam Kang1,

      Affiliated with

      • Ihil-Bong Choi1, 2,

        Affiliated with

        • Yeunhwa Gu2, 3,

          Affiliated with

          • Tomohiro Kawamura4,

            Affiliated with

            • Yoshiya Toyoda4 and

              Affiliated with

              • Atsunori Nakao4, 5Email author

                Affiliated with

                Medical Gas Research20111:11

                DOI: 10.1186/2045-9912-1-11

                Received: 23 February 2011

                Accepted: 7 June 2011

                Published: 7 June 2011

                Abstract

                Background

                Cancer patients receiving radiotherapy often experience fatigue and impaired quality of life (QOL). Many side effects of radiotherapy are believed to be associated with increased oxidative stress and inflammation due to the generation of reactive oxygen species during radiotherapy. Hydrogen can be administered as a therapeutic medical gas, has antioxidant properties, and reduces inflammation in tissues. This study examined whether hydrogen treatment, in the form of hydrogen-supplemented water, improved QOL in patients receiving radiotherapy.

                Methods

                A randomized, placebo-controlled study was performed to evaluate the effects of drinking hydrogen-rich water on 49 patients receiving radiotherapy for malignant liver tumors. Hydrogen-rich water was produced by placing a metallic magnesium stick into drinking water (final hydrogen concentration; 0.55~0.65 mM). The Korean version of the European Organization for Research and Treatment of Cancer's QLQ-C30 instrument was used to evaluate global health status and QOL. The concentration of derivatives of reactive oxidative metabolites and biological antioxidant power in the peripheral blood were assessed.

                Results

                The consumption of hydrogen-rich water for 6 weeks reduced reactive oxygen metabolites in the blood and maintained blood oxidation potential. QOL scores during radiotherapy were significantly improved in patients treated with hydrogen-rich water compared to patients receiving placebo water. There was no difference in tumor response to radiotherapy between the two groups.

                Conclusions

                Daily consumption of hydrogen-rich water is a potentially novel, therapeutic strategy for improving QOL after radiation exposure. Consumption of hydrogen-rich water reduces the biological reaction to radiation-induced oxidative stress without compromising anti-tumor effects.

                Background

                Radiotherapy is one of the major treatment options for malignant neoplasms. Nearly half of all newly diagnosed cancer patients will receive radiotherapy at some point during treatment and up to 25% may receive radiotherapy a second time [1]. While radiotherapy destroys malignant cells, it adversely affects the surrounding normal cells [2]. Acute radiation-associated side effects include fatigue, nausea, diarrhea, dry mouth, loss of appetite, hair loss, sore skin, and depression. Radiation increases the long-term risk of cancer, central nervous system disorders, cardiovascular disease, and cataracts. The likelihood of radiation-induced complications is related to the volume of the irradiated organ, the radiation dose delivered, the fractionation of the delivered dose, the delivery of radiation modifiers, and individual radiosensitivity [3]. Most radiation-induced symptoms are believed to be associated with increased oxidative stress and inflammation, due to the generation of reactive oxygen species (ROS) during radiotherapy, and may significantly affect the patient's quality of life (QOL) [2].

                Hydrogen, a therapeutic medical gas, has antioxidant properties and reduces inflammatory events in tissues [46]. Drinking liquids supplemented with hydrogen represents a novel method of hydrogen gas delivery that is easily translatable into clinical practice, with beneficial effects for several medical conditions, including atherosclerosis, type 2 diabetes, metabolic syndrome, and cognitive impairment during aging and in Parkinson's disease [711]. Currently, there is no definitive therapy to improve the QOL of patients receiving radiotherapy. Drinking solubilized hydrogen on a daily basis may be beneficial and would be quite easy to administer without complicating or changing a patient's lifestyle. We hypothesized that oral intake of hydrogen-rich water, generated via a magnesium stick, would reduce adverse events in patients receiving radiotherapy.

                Methods

                Subjects and design

                The study was a two-arm, randomized, controlled clinical trial. Patients were randomly assigned to receive either hydrogen-rich water or placebo water on the first day of radiation treatment, and received follow-up questionnaires on compliance and potential adverse effects. Eligible patients were informed of the study during scheduling of pre-radiation testing. Patient characteristics, including tumor origin and the specifics of radiotherapy, are listed in Table 1. Forty-nine subjects (33 men and 16 women) were enrolled between April and October 2006. The age of the patients ranged from 21 to 82 years (mean age 58.6 years). All patients were diagnosed either histologically or pathologically with hepatocellular carcinoma (HCC) or metastatic hepatic tumors. All participants received 5040-6500 cGy of radiotherapy for 7-8 weeks using a 6 MV system (Cyber Knife, Fanuc, Yamanashi, Japan). The planned target volume of the initial field was assessed by a localization/simulation procedure or by computed tomography (CT)-assisted planning and encompassed the primary tumors and a 2 cm margin. Blocks were used to shield normal tissue.
                Table 1

                Patient Characteristics

                 

                water

                Age

                gender

                times

                diagnosis

                isodose curve (%)

                total cGy

                volume (cc)

                collimater (cc)

                response

                 

                water

                age

                gender

                times

                diagnosis

                isodose curve (%)

                total cGy

                volume (cc)

                collimater (cc)

                response

                1

                placebo

                76

                M

                3

                3

                HCC

                80

                75

                3,900

                3,900

                2.521

                2.746

                7.5

                7.5

                NR

                 

                HW

                52

                M

                3

                liver meta of colon ca

                74

                3,600

                12.283

                15

                NR

                2

                placebo

                82

                M

                1

                HCC

                70

                1,200

                11.769

                20

                CR

                 

                HW

                56

                M

                3

                liver meta of colon ca

                85

                3,600

                2.552

                12.5

                PR

                3

                placebo

                57

                F

                3

                bile duct ca

                80

                3,000

                40.334

                30

                PR

                 

                HW

                77

                F

                3

                liver meta of colon ca

                75

                3,000

                107.136

                20

                CR

                4

                placebo

                47

                F

                9

                liver meta. of sarcoma

                80

                82

                84

                3,600

                3,600

                3,900

                10.628

                6.542

                2.673

                25

                20

                15

                NR

                 

                HW

                57

                M

                3

                HCC

                70

                3,600

                47.679

                15

                NR

                5

                placebo

                50

                F

                3

                liver meta of colon ca

                80

                3,900

                16.237

                20

                NR

                 

                HW

                66

                M

                3

                HCC

                80

                3,600

                16.216

                25

                PR

                6

                placebo

                21

                F

                3

                liver meta. of ovarian ca

                85

                3,600

                29.398

                30

                CR

                 

                HW

                57

                M

                3

                HCC

                80

                3,600

                35.303

                30

                NR

                7

                placebo

                65

                M

                3

                liver meta. of rectal ca

                70

                3,000

                182.871

                40

                PR

                 

                HW

                47

                M

                3

                HCC

                77

                3,000

                17.65

                20

                CR

                8

                placebo

                73

                M

                3

                liver meta. of rectal ca

                75

                3,600

                37.937

                20

                PR

                 

                HW

                49

                M

                3

                HCC

                80

                3,300

                53.578

                12.5

                PR

                9

                placebo

                58

                M

                3

                liver meta. of pancreatic ca

                75

                3,000

                65.637

                35

                CR

                 

                HW

                71

                F

                3

                HCC

                85

                3,000

                3.861

                10

                NR

                10

                placebo

                64

                M

                3

                HCC

                70

                3,000

                140.136

                20

                PR

                 

                HW

                45

                M

                3

                HCC

                80

                3,600

                28.286

                15

                NR

                11

                placebo

                65

                F

                3

                HCC

                70

                3,600

                48.645

                25

                PR

                 

                HW

                45

                F

                3

                liver meta. of gastric ca

                85

                3,000

                38.938

                15

                PR

                12

                placebo

                80

                M

                3

                HCC

                80

                3,000

                209.954

                25

                NR

                 

                HW

                56

                F

                3

                Adrenal metastasis of HCC

                80

                3,600

                9.494

                15

                PR

                13

                placebo

                56

                M

                3

                HCC

                85

                3,600

                15.365

                15

                CR

                 

                HW

                49

                M

                3

                Adrenal metastasis of HCC

                75

                3,000

                91.223

                20

                NR

                14

                placebo

                61

                F

                3

                HCC

                70

                3,000

                98.957

                30

                NR

                 

                HW

                60

                M

                3

                LN metastasis of HCC

                75

                3,000

                120.366

                25

                NR

                15

                placebo

                46

                M

                3

                HCC

                80

                3,000

                20.848

                25

                CR

                 

                HW

                47

                M

                3

                LN metastasis of HCC

                80

                3,000

                80.459

                25

                NR

                16

                placebo

                70

                F

                3

                HCC

                85

                3,600

                16.908

                20

                PR

                 

                HW

                50

                M

                3

                HCC

                75

                3,600

                29.422

                20

                NR

                17

                placebo

                44

                M

                3

                HCC

                85

                3,600

                16.612

                30

                NR

                 

                HW

                49

                F

                3

                HCC

                70

                3,000

                156.289

                40

                PR

                18

                placebo

                48

                M

                3

                HCC

                85

                3,000

                35.093

                20

                NR

                 

                HW

                63

                F

                3

                HCC

                75

                3,900

                5.425

                20

                NR

                19

                placebo

                76

                F

                3

                HCC

                85

                3,600

                5.75

                15

                NR

                 

                HW

                51

                M

                3

                HCC

                70

                4,000

                28.637

                35

                NR

                20

                placebo

                60

                M

                3

                HCC

                83

                3,600

                6.802

                12.5

                NR

                 

                HW

                67

                F

                3

                HCC

                80

                3,600

                20.122

                20

                PR

                21

                placebo

                77

                M

                3

                HCC

                75

                3,300

                33.282

                25

                PR

                 

                HW

                56

                M

                3

                HCC

                70

                3,600

                23.5

                20

                CR

                22

                placebo

                55

                M

                3

                HCC

                83

                3,600

                11.963

                20

                NR

                 

                HW

                78

                F

                3

                HCC

                83

                3,600

                26.456

                25

                NR

                23

                placebo

                57

                M

                3

                HCC

                70

                3,000

                75.782

                40

                NR

                 

                HW

                56

                M

                3

                HCC

                77

                3,600

                31.908

                20

                CR

                24

                placebo

                65

                M

                2

                HCC

                75

                3,000

                55.191

                25

                NR

                 

                HW

                60

                M

                3

                HCC

                70

                3,600

                36.479

                30

                PR

                            

                HW

                70

                M

                3

                HCC

                76

                3,600

                63.434

                40

                NR

                M: male, F: female, HCC: hepatocellular carcinoma, NR: no response, PR: partial response, CR: complete response, HW: hydrogen water

                Hydrogen-rich water was produced by placing a metallic magnesium stick (Doctor SUISOSUI®, Friendear, Tokyo, Japan) into drinking water (Mg + 2H2O → Mg (OH)2 + H2; final hydrogen concentration: 0.55~0.65 mM). The magnesium stick contained 99.9% pure metallic magnesium and natural stones in a polypropylene and ceramic container. The subjects were randomly assigned to groups to either drink hydrogen-rich water for 6 weeks (n = 25) or drink water containing a placebo (a casing-only stick placed in drinking water) (n = 24). Subjects were provided with four 500 mL bottles of drinking water per day and instructed to place two magnesium sticks in each bottle of water at the end of each day in preparation for consumption the following day. Participants were asked to drink 200-300 mL from one bottle each morning, and 100-200 mL every a few hours from the remaining three bottles. Subjects were instructed to reuse the magnesium sticks by transferring the sticks to a new bottle of water after use. The subjects were expected to consume 100-300 mL of hydrogen-rich water more than 10 times per day for a total minimum consumption of 1500 mL (1.5 L) and a maximum consumption of 2000 mL (2.0 L). Oral intake of hydrogen water or placebo water started on the first day of radiotherapy and continued for 6 weeks. All the patients survived through the 6 week follow-up period when the QOL questionnaire was administered. This study was conducted in accordance with Good Clinical Practice guidelines and the ethical principles of the Declaration of Helsinki (2000). The study protocol and materials were approved by the Institutional Review Board of Catholic University Medical College, and all subjects provided written informed consent prior to participation.

                QOL Assessment

                The Korean version of the European Organization for Research and Treatment of Cancer's QLQ-C30 instrument with modifications was used to evaluate global health status and create QOL scales [12]. The descriptive, mailed survey developed by our institute was used in this study. The questionnaire contains five functional scales (physical, cognitive, emotional, social, and role-functioning), three symptom scales (pain, fatigue, and nausea/vomiting), and six single items to assess additional symptoms (dyspnea, insomnia, loss of appetite, constipation, diarrhea). For all items, a response scale ranging from 0-5 was used. A higher score reflected a higher level of symptoms and decreased QOL. Assessments were performed before radiotherapy and every week for 6 weeks after the initiation of radiotherapy.

                Biomarker analysis

                The concentrations of derivatives of reactive oxidative metabolites (dROMs) and biological antioxidant power (BAP) in the peripheral blood were assessed using a free Radical Analytical System (FRAS4; H&D, Parma, Italy) on the first day of radiation therapy (week 0) and after 6 weeks of radiotherapy. Blood samples were obtained from all patients after overnight fasting. FRAS4 dROMs kits were used to measure total hydroperoxide levels, which are representative of the total dROMs produced as a result of peroxidation chain reactions of proteins, lipids, and amino acids. Results were expressed in U.CARR; 1 U.CARR is equivalent to 0.08 mg/dl of hydrogen peroxide and the value is directly proportional to the concentration, according to Lambert-Beer's law.

                Redox potential, including glutathione peroxidase and superoxide dismutase, were determined using the FRAS4 BAP test [13]. Described briefly, the samples to be tested were dissolved in a colored solution containing a source of ferric ions and a chromogenic substance (a sulfur-derived compound). After a 5-minute incubation period, the degree of discoloration and intensity of the change were directly proportional to the ability of the plasma to reduce ferric ions. The amount of reduced ferric ions was calculated using a photometer to assess the intensity of discoloration; BAP results were expressed as µmol/l of reduced Fe/l.

                Blood chemistry tests for aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase (γ-GTP), and total cholesterol, as well as blood hematology tests for red blood cell count, white blood cell count, and platelet count were conducted at week 0 and week 6 using standard assays in an accredited hospital laboratory.

                Assessment of response

                Patients underwent dynamic CT scans 1-2 months after completion of radiation treatment and tumor response was checked at 2-3 month intervals thereafter. Treatment response and local recurrence were evaluated using follow-up dynamic CT scans and serum tests for alpha-fetoprotein (AFP) and prothrombin, which is induced by vitamin K absence or antagonist-II (PIVKA-II). Tumor response was determined by the criteria established by Kwon et al. [14]. Described briefly, complete response (CR) was defined as the disappearance of any intratumoral arterial enhancement in all target lesions. Partial response (PR) was defined as at least a 30% decrease in the sum of the diameters of viable target lesions. Progressive disease (PD) was defined as an at least 20% increase in the sum of the diameters of viable target lesions or the appearance of a new lesion. Stable disease (SD) was defined as a tumor status that did not meet any of the above criteria.

                Statistical analysis

                Unpaired t tests were used to compare numerical data and the Yates 2 x 2 chi-square test or Fisher exact probability test was used to compare categorical data. Statistical analyses were performed using SAS 6.13 software (SAS Institute Inc., Cary, NC). The sample size of 49 patients was sufficient to detect a change in mean scores of RORTC QLQ-C30.

                Results

                Hydrogen water improved the QOL of patients receiving radiotherapy

                The QOL of the patients who were given placebo water deteriorated significantly within the first month of radiotherapy (Figure 1A). There were no differences between the groups in the QOL subscales for fatigue, depression, or sleep. Gastrointestinal (GI) symptoms are one of the most common complaints of patients undergoing radiotherapy and are considered to have a high impact on the patient's QOL after 6 weeks of radiotherapy. The patients consuming hydrogen water experienced significantly less appetite loss and fewer tasting disorders compared to the patients consuming placebo water. No significant difference was seen in the mean scores for vomiting or diarrhea (Figure 1B).
                http://static-content.springer.com/image/art%3A10.1186%2F2045-9912-1-11/MediaObjects/13618_2011_Article_12_Fig1_HTML.jpg
                Figure 1

                Placebo water and hydrogen water improved the QOL of patients receiving radiotherapy. A. Weekly assessment of the patients' QOL. B. Scoring system of GI symptoms after 6 weeks of radiotherapy with or without hydrogen water.

                Hydrogen water mitigated oxidative stress marker during radiotherapy

                Before treatment, there were no differences in total hydroperoxide levels, representative of total dROM levels, between the treatment groups. Radiotherapy markedly increased total hydroperoxide levels in the patients consuming placebo water. However, drinking hydrogen water prevented this increase in total serum hydroperoxide, as determined by the dROM test (Figure 2A), indicating decreased oxidative stress during radiotherapy in the patients who consumed hydrogen water. Similarly, endogenous serum antioxidant activity significantly deteriorated during radiotherapy in the patients consuming placebo water, and biologic antioxidant activity was maintained in patients who consumed hydrogen-rich water, even after 6 weeks of radiotherapy (Figure 2B).
                http://static-content.springer.com/image/art%3A10.1186%2F2045-9912-1-11/MediaObjects/13618_2011_Article_12_Fig2_HTML.jpg
                Figure 2

                Hydrogen water mitigated oxidative stress marker during radiotherapy. Antioxidative effects in patients with placebo water (n = 24) and hydrogen rich water (n = 25). The dROM level (A) represents the total level of peroxide metabolities, and BAP (B) reflects serum antioxidant capacity.

                Hydrogen water did not compromise the radiation treatment efficacies

                Tumor response to radiotherapy was similar between the treatment groups, and 12 of 24 (50.0%) patients in the placebo group and 12 of 25 (48%) patients in hydrogen water group exhibited either a completed response (CR) or a partial response (PR). There were no patients in either group with progressive disease (PD) during the follow-up period (3 months). Thus, drinking hydrogen water did not compromise the anti-tumor effects of radiotherapy.

                Hydrogen treatment did not alter liver function or blood composition during radiotherapy

                There were no significant differences in aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transpeptidase (γ-GTP) and total cholesterol levels at week 0 and week 6, regardless of the type of water consumed (Table 2), indicating that hydrogen water consumption did not alter liver function. Similarly, there were no significant differences in red blood cell count, white blood cell count, or platelet count between patients consuming hydrogen water and patients consuming placebo water (Table 3).
                Table 2

                Changes in liver function tests

                 

                Placebo

                Hydrogen water

                 

                all (n = 25)

                male (n = 17)

                female (n = 8)

                all (n = 25)

                male (n = 16)

                female (n = 9)

                AST(IU/L)

                      

                   Week 0

                24.8 ± 9.1

                25.6 ± 5.7

                23.1 ± 10.4

                25.3 ± 6.7

                25.9 ± 5.3

                23.9 ± 8.3

                   Week 6

                26.3 ± 6.7

                26.9 ± 7.1

                25.4 ± 6.8

                26.8 ± 8.2

                27.2 ± 9.9

                26.4 ± 5.1

                ALT(IU/L)

                      

                Week 0

                27.4 ± 15

                28.1 ± 11

                26.5 ± 17

                26.9 ± 8.7

                27.1 ± 6.7

                26.7 ± 10.3

                Week 6

                28.8 ± 14

                28.7 ± 16

                27.6 ± 12

                28.1 ± 6.5

                28.8 ± 7.3

                27.6 ± 9.9

                γ-GPT(IU/L)

                      

                Week 0

                61.9 ± 54.3

                62.3 ± 35.6

                60.5 ± 64.7

                62.3 ± 26.2

                62.1 ± 34.8

                62.4 ± 47.9

                Week 6

                62.8 ± 22.8

                63.2 ± 16.5

                62.7 ± 25.9

                63.6 ± 36.2

                63.9 ± 54.2

                63.2 ± 27.4

                AST(IU/L)

                      

                Week 0

                24.8 ± 9.1

                25.6 ± 5.7

                23.1 ± 10.4

                25.3 ± 6.7

                25.9 ± 5.3

                23.9 ± 8.3

                Week 6

                26.3 ± 6.7

                26.9 ± 7.1

                25.4 ± 6.8

                26.8 ± 8.2

                27.2 ± 9.9

                26.4 ± 5.1

                Table 3

                Peripheral blood cell counts

                 

                Placebo

                Hydrogen water

                 

                all (n = 25)

                male (n = 17)

                female (n = 8)

                all (n = 25)

                male (n = 16)

                female (n = 9)

                The number of leukocytes (× 102 /μL)

                      

                Week 0

                55.8 ± 15.6

                58.5 ± 12.7

                52.8 ± 16.4

                56.2 ± 16.7

                57.3 ± 17.2

                55.4 ± 15.1

                Week 6

                53.9 ± 21.4

                54.1 ± 22.7

                53.7 ± 19.8

                54.7 ± 28.7

                55.1 ± 31.2

                53.8 ± 19.4

                The number of erythrocytes (× 104 /μL)

                      

                Week 0

                474.2 ± 38.3

                492.3 ± 45.8

                460.8 ± 30.5

                482.5 ± 42.1

                496.6 ± 50.7

                472.9 ± 36.4

                Week 6

                462.1 ± 52.4

                473.8 ± 42.1

                456.4 ± 62.2

                479.5 ± 36.5

                486.4 ± 29.4

                470.7 ± 40.5

                The number of thrombocytes (×104 /μL)

                      

                Week 0

                25.7 ± 6.5

                26.4 ± 4.7

                24.7 ± 5.9

                26.4 ± 7.1

                26.9 ± 5.5

                26.1 ± 4.8

                Week 6

                24.5 ± 4.7

                25.9 ± 2.8

                23.4 ± 6.4

                25.7 ± 4.8

                26.1 ± 4.7

                25.3 ± 3.9

                Discussion

                To our knowledge, this is the first report demonstrating the benefits of drinking hydrogen water in patients receiving radiation therapy for malignant tumors. This finding may provide the foundation for a clinically applicable, effective, and safe strategy for the delivery of hydrogen gas to mitigate radiation-induced cellular injury. Patients experience GI symptoms and decreased QOL during radiotherapy. These symptoms usually occur as a result of the body repairing damage to healthy cells, are particularly common towards the end of a course of radiation treatment, and can last for some time. The symptoms and their impact on QOL can be worsened by having to travel to the hospital each day. Drinking hydrogen-rich water improved the QOL of the patients receiving radiotherapy and did not require additional hospital visits. Although overall survival of patients with malignant tumors should remain oncologists' primary concern, survival should also be interpreted in light of symptom palliation and overall QOL, because the side effects of radiotherapy may negate the putative benefit of improved survival. Oral intake of daily hydrogen-supplemented water might be a prophylactic strategy to improve QOL of the patients receiving radiotherapy.

                Although the mechanisms underlying the beneficial effects of hydrogen-rich water during radiotherapy have not been clearly elucidated, drinking hydrogen-supplemented water reduced dROM levels and maintained BAP levels in the serum, suggesting hydrogen-rich water exhibits potent systemic antioxidant activity. Previous experimental studies have linked daily consumption of hydrogen-rich water with improvement of a number of conditions in rodent models, including reducing atherosclerosis in apolipoprotein E knockout mice [10], alleviating cisplatin-induced nephrotoxicity [15], reducing vitamin C deficiency-induced brain injury [16], preventing chronic allograft nephropathy after renal transplantation [17], and ameliorating cognitive defects in senescence-accelerated mice [9] and a Parkinson's disease model [7]. In human studies, consumption of hydrogen-rich water prevented adult-onset diabetes and insulin resistance [11], as well as oxidative stress in potential metabolic syndrome [8].

                Radiotherapy is associated with an increase in ROS, followed by damage to DNA, lipids, and proteins, and activation of transcription factors and signal transduction pathways. It has been estimated that 60-70% of the ionizing radiation-induced cellular damage is caused by hydroxyl radicals [18]. Therefore, a number of trials with the goal of reducing adverse effects due to excess ROS production have been performed with antioxidants delivered during the course of radiotherapy. Supplementation with α-tocopherol improves the salivary flow rate and maintains salivary parameters [19]. Treatment with the antioxidant enzyme superoxide dismutase prevented radiotherapy-induced cystitis and rectitis in bladder cancer patients receiving radiotherapy [20]. In addition, the combined use of pentoxifylline and vitamin E reduced radiation-induced lung fibrosis in patients with lung cancer receiving radiotherapy [21]. Thus, in general, supplementation with antioxidants is likely to offer overall benefits in the treatment of adverse effects of radiotherapy. However, not all antioxidants can afford radioprotection [2224]. Furthermore, of significant concern is the finding that high doses of antioxidants administered as adjuvant therapy might compromise the efficacy of radiation treatment and increase of the risk of local recurrence of cancer [25, 26]. Hence, the relatively lower toxicity associated with the use of these antioxidant agents is appealing, but not at the cost of poor tumor control. In contrast, in this study, drinking hydrogen-rich water did not affect radiotherapy's anti-tumor effects. Our results may suggest that hydrogen water functions not only as an antioxidant, but also plays a protective role by inducing radioprotective hormones or enzymes. Although further studies are warranted to elucidate the safety of hydrogen-rich water and determine the optimal concentration of hydrogen in drinking water, as well as involved mechanisms, daily intake of hydrogen-rich water may be a promising approach for counteracting radiation-induced impairments to QOL. This therapeutic use of hydrogen is also supported by the work of Qian et al., who demonstrated that treating human lymphocyte AHH-1 cells with hydrogen before irradiation significantly inhibited ionizing irradiation-induced apoptosis and increased cell viability in vitro. They also showed that injection of hydrogen-rich saline could protect the gastrointestinal endothelia from radiation-induced injury, decrease plasma malondialdehyde and intestinal 8-hydroxydeoxyguanosine levels, and increase plasma endogenous antioxidants in vivo [27].

                Conclusions

                In conclusion, our study demonstrated that drinking hydrogen-rich water improved QOL and reduced oxidative markers in patients receiving radiotherapy for liver tumors. This novel approach of oral intake of hydrogen-rich water may be applicable to a wide range of radiation-related adverse symptoms.

                List of abbreviations

                ROS: 

                reactive oxygen species

                QOL: 

                quality of life

                Declarations

                Acknowledgements

                This research was supported by a Daimaru Research Foundation grant awarded to YG.

                Authors’ Affiliations

                (1)
                Department of Therapeutic Radiology, Gyeongsang National University Hospital, Gyeongsang Institute of Health Sciences
                (2)
                Department of Radiation Oncology, Catholic University Medical College
                (3)
                Graduate School of Health Science, Suzuka University of Medical Science
                (4)
                Department of Cardiothoracic Surgery, University of Pittsburgh
                (5)
                Department of Surgery, University of Pittsburgh

                References

                1. Ringborg U, Bergqvist D, Brorsson B, Cavallin-Stahl E, Ceberg J, Einhorn N, Frodin JE, Jarhult J, Lamnevik G, Lindholm C, Littbrand B, Norlund A, Nylen U, Rosen M, Svensson H, Moller TR: The Swedish Council on Technology Assessment in Health Care (SBU) systematic overview of radiotherapy for cancer including a prospective survey of radiotherapy practice in Sweden 2001--summary and conclusions. Acta Oncol. 2003, 42 (5-6): 357-65. 10.1080/02841860310010826.View ArticlePubMed
                2. Zhao W, Robbins ME: Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications. Curr Med Chem. 2009, 16 (2): 130-43. 10.2174/092986709787002790.View ArticlePubMed
                3. Citrin D, Cotrim AP, Hyodo F, Baum BJ, Krishna MC, Mitchell JB: Radioprotectors and mitigators of radiation-induced normal tissue injury. Oncologist. 2010, 15 (4): 360-71. 10.1634/theoncologist.2009-S104.PubMed CentralView ArticlePubMed
                4. Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, Katsura K, Katayama Y, Asoh S, Ohta S: Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007, 13 (6): 688-94. 10.1038/nm1577.View ArticlePubMed
                5. Buchholz BM, Kaczorowski DJ, Sugimoto R, Yang R, Wang Y, Billiar TR, McCurry KR, Bauer AJ, Nakao A: Hydrogen inhalation ameliorates oxidative stress in transplantation induced intestinal graft injury. Am J Transplant. 2008, 8 (10): 2015-24. 10.1111/j.1600-6143.2008.02359.x.View ArticlePubMed
                6. Huang C, Kawamura T, Toyoda Y, Nakao A: Recent Advances in Hydrogen Research as a Therapeutic Medical Gas. Free Rad Res. 2010, 44 (9): 971-82. 10.3109/10715762.2010.500328.View Article
                7. Fujita K, Seike T, Yutsudo N, Ohno M, Yamada H, Yamaguchi H, Sakumi K, Yamakawa Y, Kido MA, Takaki A, Katafuchi T, Tanaka Y, Nakabeppu Y, Noda M: Hydrogen in Drinking Water Reduces Dopaminergic Neuronal Loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Mouse Model of Parkinson's Disease. PLoS One. 2009, 4 (9): e7247-10.1371/journal.pone.0007247.PubMed CentralView ArticlePubMed
                8. Nakao A, Toyoda Y, Sharma P, Evans M, Guthrie N: Effectiveness of hydrogen rich water on antioxidant status of subjects with potential metabolic syndrome-an open label pilot study. J Clin Biochem Nutr. 2010, 46 (2): 140-9. 10.3164/jcbn.09-100.PubMed CentralView ArticlePubMed
                9. Gu Y, Huang CS, Inoue T, Yamashita T, Ishida T, Kang KM, Nakao A: Drinking hydrogen water ameliorated cognitive impairment in senescence-accelerated mice. J Clin Biochem Nutr. 2010, 46 (3): 269-76. 10.3164/jcbn.10-19.PubMed CentralView ArticlePubMed
                10. Ohsawa I, Nishimaki K, Yamagata K, Ishikawa M, Ohta S: Consumption of hydrogen water prevents atherosclerosis in apolipoprotein E knockout mice. Biochem Biophys Res Commun. 2008, 377 (4): 1195-8. 10.1016/j.bbrc.2008.10.156.View ArticlePubMed
                11. Kajiyama S, Hasegawa G, Asano M, Hosoda H, Fukui M, Nakamura N, Kitawaki J, Imai S, Nakano K, Ohta M, Adachi T, Obayashi H, Yoshikawa T: Supplementation of hydrogen-rich water improves lipid and glucose metabolism in patients with type 2 diabetes or impaired glucose tolerance. Nutr Res. 2008, 28 (3): 137-43. 10.1016/j.nutres.2008.01.008.View ArticlePubMed
                12. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, Filiberti A, Flechtner H, Fleishman SB, de Haes JC, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993, 85 (5): 365-76. 10.1093/jnci/85.5.365.View ArticlePubMed
                13. Ezaki S, Suzuki K, Kurishima C, Miura M, Weilin W, Hoshi R, Tanitsu S, Tomita Y, Takayama C, Wada M, Kondo T, Tamura M: Resuscitation of preterm infants with reduced oxygen results in less oxidative stress than resuscitation with 100% oxygen. J Clin Biochem Nutr. 2009, 44 (1): 111-8. 10.3164/jcbn.08-221.PubMed CentralView ArticlePubMed
                14. Kwon JH, Bae SH, Kim JY, Choi BO, Jang HS, Jang JW, Choi JY, Yoon SK, Chung KW: Long-term effect of stereotactic body radiation therapy for primary hepatocellular carcinoma ineligible for local ablation therapy or surgical resection. Stereotactic radiotherapy for liver cancer. BMC Cancer. 2010, 10: 475-10.1186/1471-2407-10-475.PubMed CentralView ArticlePubMed
                15. Nakashima-Kamimura N, Mori T, Ohsawa I, Asoh S, Ohta S: Molecular hydrogen alleviates nephrotoxicity induced by an anti-cancer drug cisplatin without compromising anti-tumor activity in mice. Cancer Chemother Pharmacol. 2009, 64 (4): 753-61. 10.1007/s00280-008-0924-2.View ArticlePubMed
                16. Sato Y, Kajiyama S, Amano A, Kondo Y, Sasaki T, Handa S, Takahashi R, Fukui M, Hasegawa G, Nakamura N, Fujinawa H, Mori T, Ohta M, Obayashi H, Maruyama N, Ishigami A: Hydrogen-rich pure water prevents superoxide formation in brain slices of vitamin C-depleted SMP30/GNL knockout mice. Biochem Biophys Res Commun. 2008, 375 (3): 346-50. 10.1016/j.bbrc.2008.08.020.View ArticlePubMed
                17. Cardinal JS, Zhan J, Wang Y, Sugimoto R, Tsung A, McCurry KR, Billiar TR, Nakao A: Oral Administration Of Hydrogen Water Prevents Chronic Allograft Nephropathy In Rat Renal Transplantation. Kidney Int. 2009, 77 (2): 101-9.View ArticlePubMed
                18. Vijayalaxmi , Reiter RJ, Tan DX, Herman TS, Thomas CR: Melatonin as a radioprotective agent: a review. Int J Radiat Oncol Biol Phys. 2004, 59 (3): 639-53. 10.1016/j.ijrobp.2004.02.006.View ArticlePubMed
                19. Chitra S, Shyamala Devi CS: Effects of radiation and alpha-tocopherol on saliva flow rate, amylase activity, total protein and electrolyte levels in oral cavity cancer. Indian J Dent Res. 2008, 19 (3): 213-8. 10.4103/0970-9290.42953.View ArticlePubMed
                20. Sanchiz F, Milla A, Artola N, Julia JC, Moya LM, Pedro A, Vila A: Prevention of radioinduced cystitis by orgotein: a randomized study. Anticancer Res. 1996, 16 (4A): 2025-8.PubMed
                21. Misirlioglu CH, Demirkasimoglu T, Kucukplakci B, Sanri E, Altundag K: Pentoxifylline and alpha-tocopherol in prevention of radiation-induced lung toxicity in patients with lung cancer. Med Oncol. 2007, 24 (3): 308-11. 10.1007/s12032-007-0006-z.View ArticlePubMed
                22. Xavier S, Yamada K, Samuni AM, Samuni A, DeGraff W, Krishna MC, Mitchell JB: Differential protection by nitroxides and hydroxylamines to radiation-induced and metal ion-catalyzed oxidative damage. Biochim Biophys Acta. 2002, 1573 (2): 109-20.View ArticlePubMed
                23. Prasad KN, Cole WC, Kumar B, Che Prasad K: Pros and cons of antioxidant use during radiation therapy. Cancer Treat Rev. 2002, 28 (2): 79-91. 10.1053/ctrv.2002.0260.View ArticlePubMed
                24. Ladas EJ, Jacobson JS, Kennedy DD, Teel K, Fleischauer A, Kelly KM: Antioxidants and cancer therapy: a systematic review. J Clin Oncol. 2004, 22 (3): 517-28.View ArticlePubMed
                25. Bairati I, Meyer F, Gelinas M, Fortin A, Nabid A, Brochet F, Mercier JP, Tetu B, Harel F, Abdous B, Vigneault E, Vass S, Del Vecchio P, Roy J: Randomized trial of antioxidant vitamins to prevent acute adverse effects of radiation therapy in head and neck cancer patients. J Clin Oncol. 2005, 23 (24): 5805-13. 10.1200/JCO.2005.05.514.View ArticlePubMed
                26. Meyer F, Bairati I, Fortin A, Gelinas M, Nabid A, Brochet F, Tetu B: Interaction between antioxidant vitamin supplementation and cigarette smoking during radiation therapy in relation to long-term effects on recurrence and mortality: a randomized trial among head and neck cancer patients. Int J Cancer. 2008, 122 (7): 1679-83.View ArticlePubMed
                27. Qian L, Cao F, Cui J, Huang Y, Zhou X, Liu S, Cai J: Radioprotective effect of hydrogen in cultured cells and mice. Free Radic Res. 2010, 44 (3): 275-82. 10.3109/10715760903468758.View ArticlePubMed

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                This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://​creativecommons.​org/​licenses/​by/​2.​0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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