Hydrogen eases side effects of lung cancer medicamentsScientific Research

original title: Hydrogen therapy can be used to control tumor progression and alleviate the adverse events of medications in patients with advanced non-small cell lung cancer

Published on: 05/06/2020

Abstract

Chemotherapy, targeted therapy, and immunotherapy are used to treat advanced non-small cell lung cancer. There is a lack of clinically effective methods to improve adverse events associated with such therapies. Fifty-eight adult patients participated in our study for relief of pulmonary symptoms or drug side effects. Twenty patients who refused medical treatment were equally allocated and randomly assigned to hydrogen-only (H2) and control groups. Based on tumor gene mutations and drug susceptibility test results, 10, 18, and 10 patients were included in the chemotherapy group, the targeted therapy group, and the immunotherapy group, respectively, where these treatments were combined with H2 therapy, respectively.

Patients inhale H2 4-5 hours a day for 5 months, or stop when cancer recurs. Before the start of the study, there were no significant differences in demographics (except for mutated genes in tumors) and pulmonary symptoms (except for moderate cough) among the five groups. During the first 5 months of treatment, the incidence of symptoms in the control group gradually increased, while the incidence of symptoms in the four treatment groups gradually decreased. After 16 months of follow-up, the progression-free survival in the control group was lower than that in the H2 group alone, and was significantly lower than that in the H2+ chemotherapy group, the H2+ targeted therapy group, and the H2+ immunotherapy group.

In the combination treatment group, most drug-related adverse events gradually decreased or even disappeared. The H2 inhalation method was first discovered clinically and can be used to control tumor progression and reduce drug side effects in patients with advanced non-small cell lung cancer. This study was approved by the Ethics Committee of Fuda Cancer Hospital of Jinan University on December 7, 2018 (Approval No. Fuda20181207), and was registered with ClinicalTrials.gov on January 28, 2019 (No. NCT03818347).

Research Conclusion

We found that H₂ monotherapy could prolong the PFS of patients with advanced NSCLC from 4.4 ± 1.2 months to 7.9 ± 2.2 months, suggesting that H₂ could inhibit the growth of lung cancer cells independently. This hypothesis has been bolstered by data from an in vitro and in vivo study, which confirmed that H₂ can inhibit the proliferation, migration, and invasion of the lung-cancer cell lines and tumor growth in mouse model.^[53]

These data suggested that H₂ could serve as new therapy against lung cancer. However, for patients eligible for first-line treatment, drugs will produce more pronounced effects upon tumor control. Whether a combination of drug therapy and H₂ therapy can elicit better tumor control must be studied further, but gradual reduction of most drug-associated adverse events after H₂ inhalation is clear.

Original Publication

Hydrogen therapy can be used to control tumor progression and alleviate the adverse events of medications in patients with advanced non-small cell lung cancer

DOI:  10.4103/2045-9912.285560

Ji-Bing Chen¹, Xiao-Feng Kong², Feng Mu², Tian-Yu Lu¹, You-Yong Lu³, Ke-Cheng Xu¹

Abstracts

Chemotherapy, targeted therapy, and immunotherapy are used to treat advanced non-small cell lung cancer. There is a lack of clinically effective methods to improve adverse events associated with such therapies. Fifty-eight adult patients participated in our study for relief of pulmonary symptoms or drug side effects. Twenty patients who refused medical treatment were equally allocated and randomly assigned to hydrogen-only (H2) and control groups. Based on tumor gene mutations and drug susceptibility test results, 10, 18, and 10 patients were included in the chemotherapy group, the targeted therapy group, and the immunotherapy group, respectively, where these treatments were combined with H2 therapy, respectively. Patients inhale H2 4-5 hours a day for 5 months, or stop when cancer recurs. Before the start of the study, there were no significant differences in demographics (except for mutated genes in tumors) and pulmonary symptoms (except for moderate cough) among the five groups. During the first 5 months of treatment, the incidence of symptoms in the control group gradually increased, while the incidence of symptoms in the four treatment groups gradually decreased. After 16 months of follow-up, the progression-free survival in the control group was lower than that in the H2 group alone, and was significantly lower than that in the H2+ chemotherapy group, the H2+ targeted therapy group, and the H2+ immunotherapy group. In the combination treatment group, most drug-related adverse events gradually decreased or even disappeared. The H2 inhalation method was first discovered clinically and can be used to control tumor progression and reduce drug side effects in patients with advanced non-small cell lung cancer. This study was approved by the Ethics Committee of Fuda Cancer Hospital of Jinan University on December 7, 2018 (Approval No. Fuda20181207), and was registered with ClinicalTrials.gov on January 28, 2019 (No. NCT03818347).

Results

Clinical data from patients with advanced non-small cell lung cancer receiving H2 inhalation therapy

Patients inhaled H2 daily for 5 months or stopped when the cancer recurred. Most patient characteristics, such as gender, were not significantly different within each group. However, the targeted therapy and H2 therapy groups had a higher proportion of tumor gene mutations than the other four groups (p=0.005; [Table 1].

Table 1: Patient demographics of advanced non-small cell lung cancer patients in different groups

Pulmonary signs and symptoms of advanced non-small cell lung cancer patients with H₂ inhalation treatment

There were no significant differences in lung function or KPS scores between the five groups of patients before starting H2 therapy [Table 2]. The incidence of most pulmonary symptoms (eg, mild dyspnea, noncardiac chest pain, pleural effusion, and hemoptysis) was similar between groups. The incidence of most pulmonary symptoms was higher in the control group, H2 monotherapy group, and immunotherapy H2 treatment group than in the targeted therapy H2 treatment group and chemotherapy H2 treatment group (p=0.0137).

 

Table 2: Pulmonary signs and symptoms before hydrogen therapy of advanced non-small cell lung cancer patients with H₂ inhalation treatment

Tumor-associated symptoms of advanced non-small cell lung cancer patients with H₂ inhalation treatment

The incidence of tumor-related symptoms was similar in the control and H2 monotherapy groups at the start of H2 therapy (p=0.9994). With increasing treatment time, the control group developed moderate cough (P = 0.0023), mild dyspnea (P = 0.0019), mild non-cardiac chest pain (P = 0.0006), mild pleural effusion (P = 0.0006) 0.0023) and mild hemoptysis (P=0.0028) significantly increased [Figure 2]A. Moderate cough (P=0.0014), mild dyspnea (P=0.0247), mild non-cardiac chest pain (P=0.0136), mild pleural effusion (P=0, 0015) and H2 monotherapy group The incidence of mild hemoptysis (P=0.0048) decreased significantly [Fig. 2]B.

Figure 2: Tumor-associated symptoms varied with the inhalation time of hydrogen (H₂).
Note: (A) Control group (inhalation of 33.3% oxygen gas and no H₂ (n = 10). (B) H₂ only group (inhalation of 66.7% H₂ + 33.3% O₂) (n = 10). Each tumor-associated symptom was compared using linear regression analysis.

Drug-associated adverse events of advanced non-small cell lung cancer patients with H₂ inhalation treatment

The incidence of tumor-related symptoms was similar among the three groups at the start of H2 treatment (p=0.5120), but drug-related symptoms varied widely among the three groups [Figure 3]. The prevalence of cough and non-cardiac chest pain (p=0.0013), maculopapular rash (p=0.0021), hepatobiliary disease (p=0.0064), and dizziness and headache (p=0.0111) increased with treatment duration Decreased but not diarrhea (P=0.4144) [Figure 3]A. In the targeted therapy H2 treatment group, the incidence was febrile neutropenia (p=0.0026), nausea and vomiting (p=0.0051), maculopapular rash (p<0.0001), insomnia (p=0.0144) and oral mucositis (p=0.0001) ). 0.0007) significantly decreased [Figure 3]B.The incidence of febrile neutropenia (P=0.0086), anemia and thrombocytopenia (P=0.0009), constipation and diarrhea (P=0.0053), and anorexia (P=0.0129), but not nausea and vomiting, was significantly lower in the H2 chemotherapy group (P = 0.0720; [Figure 3] C

Figure 3: Drug-associated symptoms varied with the inhalation time of hydrogen (H₂).
Note: (A) Immunotherapy-H₂ group (n = 10). (B) Target-H₂ therapy group (n = 18). (C) Chemotherapy-H₂ therapy group (n =10). Drug-associated adverse event was compared using linear regression analysis.

PFS of advanced non-small cell lung cancer patients with H₂ inhalation treatment

After 16 months of follow-up, all 58 patients had tumor progression. PFS was 4.4 ± 1.2 months in the control group, 7.9 ± 2.2 months in the H2-only group, 10.1 ± 2.6 months in the H2 immunotherapy group, 9.4 ± 3.1 months in the H2-directed therapy group, and 8.5 ± 3.0 in the H2 chemotherapy group months. PFS was longer in all four treatment groups than in the control group, and PFS was significantly prolonged in the three H2 treatment combination groups [Figure 4].

Figure 4: Comparison of progression-free survival (PFS) between groups after hydrogen (H₂) treatment.
Note: PFS of each group was compared by one-way analysis of variance and Bonferroni’s multiple comparison test. *P < 0.05, **P < 0.01, ***P < 0.001.

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