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 Table of Contents  
RESEARCH ARTICLE
Year : 2020  |  Volume : 10  |  Issue : 2  |  Page : 75-80

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


1 Fuda Cancer Hospital of Jinan University, Guangzhou; Fuda Cancer Institute, Guangzhou, Guangdong Province, China
2 Fuda Cancer Hospital of Jinan University, Guangzhou, Guangdong Province, China
3 Central Lab, Beijing Cancer Hospital, Beijing, China

Date of Submission02-Nov-2019
Date of Acceptance20-Nov-2019
Date of Web Publication05-Jun-2020

Correspondence Address:
MD Ke-Cheng Xu
Fuda Cancer Hospital of Jinan University, Guangzhou; Fuda Cancer Institute, Guangzhou, Guangdong Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2045-9912.285560

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  Abstract 


Chemotherapy, targeted therapy, and immunotherapy are used against advanced non-small cell lung cancer. A clinically efficacious method for relieving the adverse events associated of such therapies is lacking. Fifty-eight adult patients were enrolled in our trial to relieve pulmonary symptoms or the adverse events of drugs. Twenty patients who refused drug treatment were assigned equally and randomly to a hydrogen (H2)-only group and a control group. According to the results of tumor-gene mutations and drug-sensitivity tests, 10, 18, and 10 patients were enrolled into chemotherapy, targeted therapy, and immunotherapy groups in which these therapies were combined with H2-therapy, respectively. Patients underwent H2 inhalation for 4–5 hours per day for 5 months or stopped when cancer recurrence. Before study initiation, the demographics (except for tumor-mutation genes) and pulmonary symptoms (except for moderate cough) of the five groups showed no significant difference. During the first 5 months of treatment, the prevalence of symptoms of the control group increased gradually, whereas that of the four treatment groups decreased gradually. After 16 months of follow-up, progression-free survival of the control group was lower than that of the H2-only group, and significantly lower than that of H2 + chemotherapy, H2 + targeted therapy, and H2 + immunotherapy groups. In the combined-therapy groups, most drug-associated adverse events decreased gradually or even disappeared. H2 inhalation was first discovered in the clinic that can be used to control tumor progression and alleviate the adverse events of medications for 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 at ClinicalTrials.gov (Identifier: NCT03818347) on January 28, 2019.

Keywords: adverse event; chemotherapy; hydrogen; immunotherapy; non-small-cell lung cancer; NSCLC; PFS; progression-free survival; targeted drug


How to cite this article:
Chen JB, Kong XF, Mu F, Lu TY, Lu YY, Xu KC. 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. Med Gas Res 2020;10:75-80

How to cite this URL:
Chen JB, Kong XF, Mu F, Lu TY, Lu YY, Xu KC. 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. Med Gas Res [serial online] 2020 [cited 2020 Aug 3];10:75-80. Available from: http://www.medgasres.com/text.asp?2020/10/2/75/285560




  Introduction Top


Lung cancer is the most prevalent form of cancer-related disease worldwide, of which non-small-cell lung cancer (NSCLC) accounts for ~85%.[1] Many patients are at an advanced stage of lung cancer when the diagnosis is made,[2] and progression-free survival (PFS) is usually < 6 months.[3] In these cases, the tumors cannot be resected; therefore, chemotherapy,[4] targeted therapy[5] and immunotherapy[6] are common treatment options. Each treatment has different indications, and also produces different adverse events. Serious adverse events (e.g., severe granulocytopenia,[7] thrombocytopenia,[8] abnormal liver function[9]) often lead to significant changes in vital signs and patients are forced to stop or change medications.

Hydrogen (H2) is an anti-inflammatory, antioxidant, and antiapoptotic molecule. It can diffuse into mitochondria, neutralize reactive oxygen species selectively,[10],[11] and restore cell viability by regulating expression of various genes.[12] In animal experiments, H2 has been demonstrated to alleviate the serious adverse events caused by chemotherapy,[13],[14] and targeted therapy.[15] H2 has been used in clinical trials of multiple non-neoplastic diseases, indicating the safety of H2 gas inhalation.[16],[17]

In the present study, H2 therapy was used to control cancer progression and alleviate the adverse events of multiple standard therapies in patients with advanced NSCLC.


  Subjects and Methods Top


The inclusion and exclusion criteria

This clinical trial was registered at ClinicalTrials.gov (Identifier: NCT03818347) on January 28, 2019. The enrolled patients were divided into five groups according to the precise medical test results of tumors. The inclusion criteria were patients with: stage-III or -IV NSCLC diagnosed by imaging and pathology with specialist doctor; tumor number 1–6; maximum tumor length < 2 cm; Karnofsky performance status (KPS) score ≥ 70; expected survival time > 6 months; platelet count ≥ 80 × 10[9]/L; white blood cell count ≥ 3 × 10[9]/L; neutrophil count ≥ 2 × 10[9]/L; hemoglobin ≥ 80 g/L. The exclusion criteria were patients with: a cardiac pacemaker; brain metastasis; grade-3 hypertension or diabetic complications; severe cardiac and pulmonary dysfunction. This study protocol received ethical approval from the Ethics Committee of Fuda Cancer Hospital of Jinan University on December 7, 2018 (approval No. Fuda20181207). Written informed consent was obtained from each patient.

Subjects

Between June and September 2019, 58 patients with advanced NSCLC at Fuda Cancer Hospital of Jinan University met the inclusion criteria mentioned above and were enrolled in the study. Thirty-four patients had surgery before enrollment, and 24 patients were in advance stage when diagnosis.

Immunohistochemical assays of the ratio of programmed cell death-1: programmed cell death-1 ligands, tumor mutation burden, and microsatellite instability in tumor specimens were undertaken. Based on the results, 10 patients were administered a drug based on antibodies against programmed cell death-1 (Nivolumab [Opdivo®, Bristol-Myers Squibb, New York, NY, USA] or Pembrolizumab [Keytruda®, Merck, Kennyworth, NJ, USA]). Through detection of gene mutations in tumor specimens, 18 patients were selected to be given targeted therapy. Patients with a mutation in the epidermal growth factor receptor gene were administered Osimertinib (Tagrisso®, AstraZeneca, London, UK), Gefitinib (Iressa®, AstraZeneca) or Erlotinib (Tarceva®, Roche, Basel, Switzerland). Patients with a mutation in the anaplastic lymphoma kinase gene or receptor tyrosine kinase-1 gene were administered Crizotinib (Xalkori®, Pfizer, New York, NY, USA). Based on the data of drug-sensitivity tests, 10 patients were administered chemotherapy (Cisplatin or Carboplatin [both from Qilu Pharmaceutical, Haikou, Hainan Province, China]).

The remaining 20 patients who were not sensitive to common drugs or who failed to respond to treatment by common drugs were distributed evenly in the H2-monotherapy group or control group. Three groups of patients who had H2 treatment combined with another treatment (immunotherapy, targeted therapy or chemotherapy) started therapy before enrollment of our clinical trial. Most of those patients experienced significant effects on cancer-related lung symptoms after taking combination therapy, but new drug-related adverse events emerged. Lung symptoms or drug-related adverse events were compared before and after H2 treatment. The comparison of lung symptoms before hydrogen treatment and the changes of tumor or drug-related symptoms in each group after hydrogen treatment are shown in [Figure 1]. This study followed the Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) Statement.
Figure 1: Symptom comparison of patients in each group before and after hydrogen treatment.
Note: Chemo: Chemotherapy; H2: hydrogen; Immuno: immunotherapy;
NSCLC: non-small-cell lung cancer; Target: targeted therapy.


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H2 inhalation

H2 was produced by a H2–oxygen nebulizer (H2 66.7% and oxygen 33.3%; maximum gas flow, 3 L/min; AMS-H-03, Shanghai Asclepius Meditec, Shanghai, China). The control group underwent a sham procedure (H2 0% and oxygen 33.3%; maximum gas flow 3 L/min; Shanghai Asclepius Meditec). Enrolled patients inhaled the gas mixture for 4–6 hours every day and underwent imaging examination every month until the existing lesions progressed significantly or new metastases appeared. PFS was calculated from the start of H2 inhalation to tumor progression. All patients received computed tomography or magnetic resonance examination every month. If the existing tumors grew up significantly or new metastases appeared, it is considered as tumor progression.

Pulmonary symptoms and drug-associated adverse events

The respiratory function of enrolled patients before H2 therapy was assessed by very experienced respiratory physicians using a pulmonary function tester (Autospiro AS-507; Minato Medical Science, Tokyo, Japan). Pulmonary tumor-related symptoms and the KPS score of all patients before H2 inhalation were evaluated. The adverse events of chemotherapy, targeted therapy or immunotherapy were assessed by the same respiratory physicians according to Common Terminology Criteria for Adverse Events 5.0.

Statistical analyses

Before H2 treatment, the demographics and tumor-associated symptoms of patients were compared using chi-squared and Fisher's exact tests; respiratory function and the KPS score were compared using one-way analysis of variance and Bonferroni's multiple comparison test. After H2 treatment, each tumor-associated symptom and drug-associated adverse event was compared using linear regression analysis; the PFS of each group was compared by one-way analysis of variance and Bonferroni's multiple comparison test. P < 0.05 was considered significant difference. Analyses were done using Prism 5.0 (GraphPad, San Diego, CA, USA).

RESULTS

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

Patients underwent H2 inhalation per day for 5 months or stopped the inhalation when cancer relapsed. There was no significant difference in most patient characteristics (e.g., sex) in each group. However, the targeted therapy–H2-therapy group 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

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

Before the start of H2 therapy, there was no significant difference in pulmonary function or the KPS score among the five groups of patients [Table 2]. The prevalence of most pulmonary symptoms (e.g., mild dyspnea, non-cardiac chest pain, pleural effusion, and hemoptysis) was similar among groups. The prevalence of most pulmonary symptoms in the control group, H2-monotherapy group, and immunotherapy–H2-therapy group was higher than that in the target therapy–H2-therapy group and chemotherapy–H2-therapy 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

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

At the beginning of H2 treatment, the prevalence of tumor-associated symptoms in the control group and H2-monotherapy group was similar (P = 0.9994). With prolongation of the treatment time, in the control group, the prevalence of moderate cough (P = 0.0023), mild dyspnea (P = 0.0019), mild non-cardiac chest pain (P = 0.0006), mild pleural effusion (P = 0.0023), and mild hemoptysis (P = 0.0028) increased significantly [Figure 2]A. In the H2-monotherapy group, the prevalence of 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 mild hemoptysis (P = 0.0048) decreased significantly [Figure 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.


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

At the beginning of H2 treatment, the prevalence of tumor-associated symptoms in the three groups was similar (P = 0.5120), but drug-associated symptoms in the three groups were quite different [Figure 3]. With the prolongation of treatment time, 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) decreased significantly, but diarrhea did not (P = 0.4144) [Figure 3]A. In the target therapy–H2-therapy group, the prevalence febrile granulocytopenia (P = 0.0026), nausea and vomiting (P = 0.0051), maculopapular rash (P < 0.0001), insomnia (P = 0.0144), and oral mucositis (P = 0.0007) decreased significantly [Figure 3]B. In the chemotherapy–H2-therapy group, the prevalence of febrile granulocytopenia (P = 0.0086), anemia and thrombocytopenia (P = 0.0009), constipation and diarrhea (P = 0.0053) and anorexia (P = 0.0129) decreased significantly, but nausea and vomiting did not (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.


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

After 16 months of follow-up, all 58 patients developed tumor progression. PFS for the control group was 4.4 ± 1.2 months, whereas that for the H2-only group was 7.9 ± 2.2 months, H2-immunotherapy group was 10.1 ± 2.6 months, H2-targeted therapy group was 9.4 ± 3.1 months, and H2-chemotherapy group was 8.5 ± 3.0 months. PFS of the four treatment groups was longer than that of the control group, and that of the three H2 therapy-combination groups was prolonged significantly [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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  Discussion Top


Molecular H2 has been used to treat pulmonary symptoms in animal models of acute lung injury,[18],[19],[20],[21] asthma[22] and chronic obstructive pulmonary disease.[23],[24],[25] The principle of H2 therapy includes inhibition of secretion of cytokines such as interleukin-4, interleukin-13,[22] interleukin-6 and tumor necrosis factor-α.[15] H2 therapy can alleviate pulmonary inflammation without impairing anti-tumor effects.[14],[26] Therefore, H2 gas can be adopted as adjuvant therapy to suppress these symptoms.

Chemotherapy, targeted therapy, and immunotherapy are first-line treatments against advanced NSCLC.[27],[28],[29] The vastly increased generation of reactive oxygen species during treatment is believed to contribute to adverse events, resulting in oxidative stress, inflammation and apoptosis.[30],[31] In the present study, H2 therapy was shown to alleviate drug-related adverse events, most of which have been reported in animal models, including lung injury caused by various factors,[18],[19],[20],[21] hepatobiliary diseases,[32],[33],[34] maculopapular rash,[35] diarrhea and constipation,[36],[37],[38] nausea and vomiting,[39],[40] oral mucositis,[41],[42] anemia,[43] thrombocytopenia,[44] and anorexia.[45] We found that the prevalence of insomnia, dizziness and headache could be reduced significantly after H2 inhalation, which could be related to relief of diseases of the central nervous system, such as cerebral hemorrhage,[46],[47],[48] Parkinson's disease[49],[50] and Alzheimer's disease,[51],[52] observed in animal experiments. The mechanism of action observed in animal experiments could be used as a reference for clinical research. Surprisingly, H2 therapy, which is non-toxic and can alleviate adverse events in multiple organs simultaneously, has been used rarely.

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.

Several delivery methods of molecular H2 are available and convenient: inhalation, drinking H2-dissolved water, injection with H2-saturated saline, and taking a “H2 bath.”[54] H2 is non-toxic, inexpensive, can be administered readily, can diffuse into tissues and cells[55] and cross the blood–brain barrier.[56] Hence, H2 could be used to treat tumors of the head, neck and chest. Because of the risk of explosion of H2 and oxygen mixed in air, often such gas mixtures are inhaled using catheters and masks whereas, in animal experiments, drinking or injection of H2-dissolved water is employed. Use of a machine with a sufficiently high flow rate (3 L/min) and inhalation duration every day (4–6 hours) of H2 in this trial may enable control of tumor growth and reduce the prevalence of adverse events of drugs.

In general, H2 inhalation was first discovered in the clinic that can be used to control tumor progression and alleviate the adverse events of medications in patients with advanced NSCLC. The main limitation of this study is that the number of patients enrolled is relatively small, and more accurate patient benefits are still awaiting the results of large samples. Whether this therapeutic effect can be improved further, as well as determination of the synergistic effect of drugs and H2 therapy, must be explored further.

Author contributions

Design of the study: KCX and YYL; data collection: XFK; data analysis: FM and TYL; manuscript writing: JBC. All authors approved the final version of the manuscript.

Conflicts of interest

None declared.

Financial support

None.

Institutional review board statement

This study protocol received ethical approval from the Ethics Committee of Fuda Cancer Hospital of Jinan University on December 7, 2018 (approval No. Fuda20181207) and conformed to the specifications of the World Medical Association's Declaration of Helsinki.

Informed consent statement

The authors certify that they have obtained all appropriate patient consent forms. In the form the patients have given their consent for the images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity.

Reporting statement

This study followed the Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) Statement.

Copyright transfer agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices). Study protocol and informed consent form will be available immediately following publication, without end date. Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be available indefinitely at www.figshare.com.

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Peer review

Externally peer reviewed.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.



 
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