Hydrogen-controlled cancerCercetare Științifică
“Real world survey” of hydrogen-controlled cancer: a follow-up report of 82 advanced cancer patients
Advanced cancer treatment is a huge challenge and new ideas and strategies are required. Hydrogen exerts antioxidant and anti-inflammatory effects that may be exploited to control cancer, the occurrence and progression of which is closely related to peroxidation and inflammation. We conducted a prospective follow-up study of 82 patients with stage III and IV cancer treated with hydrogen inhalation using the “real world evidence” method. After 3–46 months of follow-up, 12 patients died in stage IV. After 4 weeks of hydrogen inhalation, patients reported significant improvements in fatigue, insomnia, anorexia and pain. Furthermore, 41.5% of patients had improved physical status, with the best effect achieved in lung cancer patients and the poorest in patients with pancreatic and gynecologic cancers. Of the 58 cases with one or more abnormal tumor markers elevated, the markers were decreased at 13–45 days (median 23 days) after hydrogen inhalation in 36.2%. The greatest marker decrease was in achieved lung cancer and the lowest in pancreatic and hepatic malignancies. Of the 80 cases with tumors visible in imaging, the total disease control rate was 57.5%, with complete and partial remission appearing at 21–80 days (median 55 days) after hydrogen inhalation. The disease control rate was significantly higher in stage III patients than in stage IV patients (83.0% and 47.7%, respectively), with the lowest disease control rate in pancreatic cancer patients. No hematological toxicity was observed although minor adverse reactions that resolved spontaneously were seen in individual cases. In patients with advanced cancer, inhaled hydrogen can improve patients’ quality-of-life and control cancer progression. Hydrogen inhalation is a simple, low-cost treatment with few adverse reactions that warrants further investigation as a strategy for clinical rehabilitation of patients with advanced cancer. The study protocol received ethical approval from the Ethics Committee of Fuda Cancer Hospital of Jinan University on December 7, 2018 (approval number: Fuda20181207).
Side-effects of 82 advanced cancer patients treated with hydrogen inhalation rehabilitation
Of the 29 patients treated with hydrogen inhalation alone, no hematological toxicity was found (data not shown for blood routine test), 1 patient developed stomach discomfort and chills, 1 patient developed dizziness (which disappeared spontaneously after several days). Of the 53 patients treated with hydrogen inhalation combination treatments, 1 patient developed headache (which disappeared spontaneously within 3–5 days), 1 developed occasional epistaxis (minor bleeding and gradually resolved), and 1 patient reported dryness of the nasal cavity, which disappeared a few hours after the inhalation stopped.
Discussion Investigations of the potential of hydrogen to treat tumors have a long history and a great deal of evidence. As early as 1975, Dole et al.[19] reported that hydrogen inhibited cancer. Nude mice with cutaneous squamous cell carcinoma were administered a mixture of 97.5% hydrogen and 2.5% oxygen (at pressure of 8 atmospheres), and the tumor shrank significantly after 2 weeks, while the control group receiving hyperbaric oxygen-helium showed no such changes. In 2008, Saitoh et al.[20] reported that neutral pH hydrogen-enriched electrolytic water inhibited the colony formation efficiency and colony size of human HSC-4 tongue cancer cells while having no significant inhibitory effect on normal tongue epithelioid cells and also inhibited the growth and migration ability of human HT-1080 fibrosarcoma cells. In 2009, Saitoh et al.[21] also reported that enhanced platinum-colloid hydrogen-containing water had an inhibitory effect on the colony formation and size of human HSC-4 tongue cancer cells. In 2011, Zhao et al.[22] found that hydrogen prevented the occurrence of radiation-induced lymphoma. In 2015, Runtuwene et al.[23] reported that hydrogen increased the survival rate of colon 26 carcinoma tumor-bearing mice, induced apoptosis of cancer cells, and enhanced the sensitivity of colon cancer cells to 5-fluorouracil. Our observations of 82 patients with advanced cancers who received hydrogen inhalation therapy with spontaneous breathing suggest that hydrogen therapy acts in four ways. First, hydrogen inhalation therapy improves the quality-of-life of patients. After hydrogen inhalation for 2 weeks, there was significant improvement in breathing, appetite, fatigue and insomnia and after 4 weeks, significant improvements in pain, constipation and diarrhea were observed. Second, hydrogen inhalation therapy can improve physical fitness. After 3 months, lung cancer patients showed the most significant physical improvement, whereas the poorest effect was observed for patients with gynecological and pancreatic cancers. Third, hydrogen inhalation therapy can reduce tumor markers. After 3 months, lung cancer patients showed the most significant reduction in markers, whereas the poorest effect was observed for patients with gynecological, liver and pancreatic cancers. Fourth, hydrogen inhalation therapy can control cancer progression. After 3 months, the tumor control rate of stage III patients was much higher than that of stage IV patients, with the best effect achieved in patients with lung cancer and the worst in those with pancreatic cancer.
The treatment of advanced cancer is a major challenge. Of the cancer drugs approved by the US and European drug administrations, 67% and 57% showed no evidence of long-term survival and improved quality-of-life, respectively.[24],[25] Liang et al.[26] found that the tumor microenvironment associated with chemo- and radiotherapy enhanced the malignancy of cancer cells leading to a stem-like phenotype. In a study of 413 patients with brain metastasis of different causes, Amelot et al.[27] found that anticancer drugs, especially paclitaxel and its derivatives, promoted brain metastasis and reduce disease-free survival of patients. A recent review suggested that all commonly used treatments, including radiotherapy, chemotherapy, fine-needle puncture, and surgery, can cause an increase in circulating tumor cells and promote cancer progression and distant metastasis.[28] Thus, the positive effects of hydrogen inhalation on cancer patients are very encouraging.
According to our follow-up observations, the effect of hydrogen on the control of cancer is not only related to tumor type, but also to the mode of delivery. In this study, hydrogen was inhaled at 66.7%, with a flow rate of 3000 mL/min. Since Ohsawa et al.[29] reported in 2007 that inhaling 2% hydrogen can prevent cerebral ischemia/reperfusion injury, most researchers have used 1–4% hydrogen to study the molecular biological effects of hydrogen. Reports of the effects of high pressure or high concentration hydrogen are rare, although Dole et al.[19] reported that 97.5% hydrogen delivered under 8 atmospheres successfully inhibited skin squamous cell carcinoma. In addition, the extremely high diffusivity of hydrogen provides a guarantee of its rapid delivery throughout the body, as well as a higher requirement for daily and total inhalation time. Yamamoto et al.[30] studied the distribution of hydrogen in rats after continuous inhalation at 3%. The hydrogen concentration in muscle gradually increased with time for the first 20 minutes, reaching the highest concentration in liver and the lowest in kidney. The inhalation time in this study exceeded 3 hours per day, with some patients receiving treatment for 8 hours continuously. It can be speculated that this may account for the fall in tumor markers at 13–45 days (median 23 days) and the appearance of CR and PR at 21–80 days (median 55 days). This is the first report of hydrogen inhalation therapy resulting in decreased tumor markers and tumor shrinkage. Furthermore, in this study, patients inhaled a mixture of hydrogen and oxygen, not pure hydrogen. Hypoxia can induce metabolic modification and promote the progression of malignant tumor adaptively. Conversely, improving hypoxia may inhibit cancer progression.[31],[32] Thus, our findings demonstrate that inhaling oxygen along with hydrogen helps control cancer progression. Finally, hydrogen can be delivered through inhalation, drinking hydrogen-rich water and injecting hydrogen-rich saline. Hydrogen is an inert gas and its solubility in water is very low, so it is difficult to ensure that the required concentration in tissues is achieved by drinking hydrogen-rich water. It has been reported that hydrogen in the brain is undetectable after drinking hydrogen-rich water.[33] Although hydrogen-rich saline injection can rapidly increase the concentration of hydrogen in the blood, continuous infusion of large amounts of saline will cause water-salt retention. Hydrogen inhalation is the simplest method of delivery and inhaling 66.7% hydrogen can achieve rapid rises in hydrogen concentration in tissues, generally reaching a peak of 520 μM within 30 minutes. Sustained hydrogen inhalation maintains high blood levels, equivalent to 600 μM which inhibits cancer cells growth in vitro.[34] The efficiency of hydrogen inhalation is easily affected by the inhalation tool (the efficiency of masks is higher than that of a nasal catheter), the evenness and stability of respiration, and the state of the basic lung function.
In 2014, Hanahan[35] criticized the use of the term “cancer war,” which increased the use of toxic drugs or overly aggressive treatment for incurable cancer. This term resulted in many patients with advanced cancer receiving highly-recommended treatments with severe side-effects rather than being offered access to palliative care. Haines[36] proposed that the time has come to change the term “cancer war.” The selective antioxidant, anti-inflammatory, and signal-conditioning effects of hydrogen may play a major role in improving the cancer microenvironment.[37] More recently, molecular hydrogen has also been associated with immune function, reviving CD8+ T cells in an exhausted state by maintaining mitochondrial function and restoring their anti-tumor function, thus improving the prognosis of patients with advanced cancer.[38] Hydrogen application is simple, with low cost and few adverse reactions, which is an important advantage for patient-centered, family-based home rehabilitation.
This follow-up observation study is the first to show that inhaling high concentrations hydrogen can improve quality-of-life and physical fitness and control cancer progression in patients with advanced cancer. To ensure therapeutic effectiveness, the inhaled hydrogen should be delivered at sufficiently high concentrations to rapid allow entry into tissues, and with enough time to produce a dose-accumulation effect. In this report, we emphasize the importance of rehabilitation and auxiliary intervention, rather than treatment in the general sense. However, more patients of each kind of cancers are required to validate this approach. Further investigations will also clarify issues such as the optimal treatment regimen (dose, duration, mode of delivery and effectiveness of hydrogen rehabilitation combined with mainstream treatment) and the mechanism by which of hydrogen treatment controls cancer (such as removal of reactive oxygen radicals and control of inflammation). This information is important for the development of effective hydrogen therapy for patients with advanced cancer.
Chen JB, Kong XF, Lv YY, et al. “Real world survey” of hydrogen-controlled cancer: a follow-up report of 82 advanced cancer patients. Med Gas Res. 2019 Jul-Sep;9(3):115-121.
