Hydrogen inhalation: a potential treatment for radiotherapy/chemotherapy-induced hearing loss in cancer patients

Background: Isolated radiotherapy (RT), cisplatin alone, or RT with concurrent cisplatin therapy are all standard potential treatment regimens for patients with head and neck cancers.1 Despite these treatments being commonly utilized, both RT in the facial region as well as the use of cisplatin for head and neck cancers are known for their potential to cause ototoxicity as an adverse effect of treatment.1,2 Hearing loss as a result of this ototoxicity, one of the expected treatment-induced clinical outcomes, can irreversibly affect the patient’s quality of life.1 For these patients, the conventional treatment for this hearing loss includes surgical interventions such as cochlear implantation and implantation of osseointegrated hearing aids. Nevertheless, complications after surgical treatment exist, including local inflammation and even bone exposure due to overgrowth. Conversely, non-invasive treatment options are very limited; in this article, we aim to bring attention to a potential non-invasive therapeutic approach for anti-cancer treatment-induced hearing loss.

Hearing complications following the administration of anti-cancer treatment are believed to be the result of inflammation in the inner ear and oxidative stress-induced apoptosis of sensory hair cells.3 Hydrogen boasts an antioxidative effect that could potentially reduce such oxidative stress,4 in this case, potentially alleviating hearing loss by preventing the apoptosis of sensory hair cells. When compared to other antioxidative agents, the highly diffusive nature of hydrogen gas provides better access to the inner ear. This deeper penetration of molecules allows hydrogen to diffuse through membranes and ultimately neutralize intracellular cytotoxic radical oxidative species (ROS).4 Fortunately, in stark contrast to its derivative, hydrogen sulfide, hydrogen molecule is known as a non-toxic substance, which is relatively safe for patients even when administered at high concentrations.

Hydrogen therapy is able to alleviate hearing loss in patients who have undergone radiotherapy or received cisplatin, a chemotherapy drug known for its damaging effects on hearing (Figure 1).1 It works by reducing oxidative stress by effectively neutralizing harmful ROS while preserving the beneficial ones. In addition, hydrogen therapy has anti-inflammatory effects, helping to regulate inflammatory pathways and reduce inflammation in the cochlea. Furthermore, hydrogen therapy plays a crucial role in protecting cochlear hair cells from damage caused by oxidative stress and inflammation. Recent advancements in this field include the optimization of delivery methods, the exploration of combination therapies, and the development of targeted delivery systems to enhance both the efficacy and safety of hydrogen therapy.

Figure 1.

Process of hydrogen therapy.

The effects of cisplatin and radiotherapy in generating free radicals disrupt sensory hair cells within the cochlea. This damage can potentially be mitigated through hydrogen therapy, in which hydrogen molecules neutralize reactive oxygen species. Created with Procreate. ROS: Radical oxidative species.

Methods: An in vitro study, a clinical series of 3 patients regarding the clinical use of hydrogen therapy in RT-induced hearing loss, a prospective study of 17 patients, and 2 hydrogen therapy animal studies on cisplatin-induced hearing loss were compiled and analyzed within this review. The quality of the animal studies was evaluated by the SYRCLE risk of bias tool.

Results: The in vitro study conducted by Kikkawa et al.5 suggested that hydrogen molecules are capable of protecting the sensory hair cells from cisplatin-induced toxicity. In this study, mouse cochleas were harvested and cultured in Eagle’s medium, supplemented with glucose and penicillin G, before being exposed to cisplatin and some explants being subsequently treated with hydrogen.5 Once complete, a cell survival assay was performed to examine the hair-cell loss in the cochlea in different test groups.5 Additionally, to explain the pathophysiology and mechanism of action, the formation of hydroxyl radicals and peroxynitrite was measured in different groups; results have shown that the production of both radicals was statistically impeded in the case of hydrogen administration. These results suggest that hydrogen had a significant effect in reducing free radical concentration and, thereby, its associated damage.5

Regarding cisplatin-induced hearing loss, a reduction of cisplatin-induced ototoxicity on functional, cellular, and subcellular levels was observed following hydrogen inhalation in animal studies.6 In the study performed by Qu et al., an animal model of cisplatin-induced hearing loss was treated with 2% hydrogen gas; gas was administered twice for 60 minutes at the first and sixth hours following cisplatin exposure, and auditory brainstem response was set as an indicator to evaluate the auditory status of the subjects. In those treated, an attenuation of cisplatin-induced hearing loss was observed, and histologically, treatment of this loss with 2% hydrogen gas has been shown to considerably alleviate cisplatin-induced hair cell damage within the organ of Corti.6 Similar outcomes, such as the reduction of cisplatin-induced electrophysiological threshold shifts and hair cell loss, were replicated in a later study performed by Fransson et al.2

Despite limited animal and preliminary studies on the use of hydrogen to treat RT-induced hearing loss, one case report did attempt to treat three patients with the condition.7 The patients reported improvement in perceived auditory function and pure-tone audiometry after the treatment. Nevertheless, significant changes were not observed in the tympanogram and otoscopy, which suggested that the improvement might be purely functional and may not last after cessation of the therapy.7 Recently, Kong et al. conducted a prospective study of 17 patients on the topic of hydrogen therapy in the setting of anti-cancer treatment hearing loss; results from this study support the previous findings, with the vast majority of patients self-reporting hearing improvement following treatment, with insignificant findings on both otoscope and tympanogram.8

The SYRCLE risk of bias tool was used to assess the quality of the animal studies and determine their strengths and limitations (Table 1). Both studies by Fransson et al. and Qu et al. described a random component to sequence generation, reported baseline similarities of the different animal groups, and were free of selective outcome reporting.2,6 However, other requirements were not as consistent: both studies did not use randomization for outcome assessment and were unclear as to whether the different animal groups were adequately concealed or if outcome assessors were blinded.

Table 1.

SYRCLE’s risk of bias tool for animal studies checklist performed on two studies

Quality criteria		References
		Fransson et al.2	Qu et al.6
Selection bias	1. Sequence generation	Y	Y
	2. Baseline characteristics	Y	Y
	3. Allocation concealment	U	U
Performance bias	4. Random housing	U	N
	5. Blinding	N	U
Detection bias	6. Random outcome assessment	N	N
	7. Blinding	U	U
Attrition bias	8. Incomplete outcome reporting	N	Y
Reporting bias	9. Selective outcomes reporting	Y	Y
Other sources of bias		N	Y

Y denoted the criterion was met (low risk of bias); N denoted the criterion was not met (high risk of bias); U denoted unclear fulfilment.

In the study by Fransson et al.,2 the authors were unclear as to whether or not the animals were randomly housed during the experiment. Furthermore, as a result of the study design, the investigators were unlikely to be blinded to the knowledge of the intervention each animal received during the experiment. Additionally, incomplete outcome data were not adequately addressed, as not all animals were used in the analysis, and missing outcome data were not balanced across intervention groups. Other sources of bias included the presence of contamination in some samples for metabolomics analysis of scala tympani perilymph.

In the study by Qu et al.,6 despite the death of one animal in the Cisplatin group, all animals were included in the analysis. However, the authors did not report random housing for animals during the experiment. Additionally, the study design was different from the one conducted by Fransson et al. in that groups received room air exposure and saline as alternatives to N2 and Cisplatin, respectively.2 However, the authors were unclear as to whether investigators were blinded by the knowledge of which intervention each animal received during the experiment.

Discussion: The potential rationale of cisplatin and RT-induced hearing loss: Although the pathophysiology of cisplatin and RT-induced hearing loss has not been well-studied, several studies have proposed that the hearing loss experienced may be the result of intracellular ROS accumulation as well as inner ear inflammation.3,9 Cisplatin and RT are believed to elevate ROS and thereby trigger oxidative stress-induced apoptosis of the sensory hair cells.3,9 Meanwhile, RT-induced hearing loss could possibly be due to the injury of cochlear cells via ionizing radiation.3 Exposure to ionizing radiation can either cause DNA damage directly or via ionization of water molecules into ROS, which results in oxidative damage of the DNA and ultimately, cell death. Subsequently, damage-associated molecular pattern molecules are released by dead cells to recruit additional immune cells, including macrophages, resulting in enhanced inflammation.3 The immune system interacts with ROS and induces further cell death within the cochlea via p53 and mitogen-activated protein kinase signaling pathways.3

Unlike ionizing radiation, cisplatin requires access within the cells to cause cell injury. A study has shown that cisplatin can enter sensory hair cells through mechanoelectrical transduction channels and thereby trigger the increase of intracellular ROS.9 Increased oxidative stress typically leads to DNA damage, and, consequently, cell death. Both cisplatin and RT may elevate intracellular ROS; increased oxidative stress is believed to play a major role in cisplatin and RT-induced hearing loss. Thus, it is logical to deduce that a reduction in ROS with the use of antioxidants could potentially reverse the chain of events and reduce or prevent cochlear cell death.

Lastly, a previous study on pediatric patients suggested that the severity of cisplatin-induced hearing loss has a strong correlation with age. It has been shown that younger patients, those under 4 years of age who received cisplatin treatment, are more prone to hearing loss and typically experience more severe symptoms.10 It has been postulated that this is because immature cochlea cells are more vulnerable to the ototoxic effect of cisplatin.10 Alternatively, this could also be explained by the age-related pharmacokinetics of cisplatin.10

The antioxidative effect of hydrogen molecules: Based on the proposed pathophysiology of cisplatin and RT-induced hearing loss, the administration of antioxidative agents could prevent cell death at the cochlea. The antioxidative and cytoprotective effects of hydrogen molecules have been illustrated in previous studies.11,12 The therapeutic effect of hydrogen molecules was first demonstrated in a rat model with oxidative stress-induced brain injury due to focal ischemia and reperfusion.11 In addition to the treatment of hearing loss, the application of hydrogen, including via inhalation of hydrogen molecules and infusion of hydrogen-rich saline, has been shown to successfully suppress or reverse neural cell injury in the animal model, suggesting that hydrogen could potentially be a candidate for antioxidative therapy for other cell injuries.11

Furthermore, the study also suggested that hydrogen molecules can effectively diffuse across membranes, allowing them to reduce cytotoxic ROS.11 This result is later replicated in several clinical and animal studies on different diseases and the therapeutic activity of hydrogen molecules was compared with other antioxidative agents; these agents included hyperbaric/normobaric oxygen and hydrogen sulfide.12 Unlike hydrogen sulfide and other alternatives, hydrogen molecules do not pose cytotoxicity, even at high concentrations. Thus, it is a safer option when compared to other antioxidative agents.12

Clinical approach: Preliminary studies of hydrogen therapy have shown promising results supporting the feasibility and potential efficacy of the treatment approach. Significant attenuation of cisplatin-induced hearing loss was observed in the animal studies.2,6 Cisplatin-induced pathophysiological conditions, such as electrophysiological threshold shifts, reduction of sensory hair cells, and reduced synaptophysin immunoreactivity in the synaptic region around the inner and outer sensory hair cells, were alleviated upon hydrogen inhalation.2,5

Hydrogen-oxygen therapy was also performed by Chen et al.7 in 2019. In this study, the hearing condition of all three patients was reportedly improved without the presence of serious adverse effects.7 Additionally, a recently published prospective study of 17 patients supported the results of the case report.8 However, it is important to note that, in isolation, the published case series and prospective study are insufficient to provide fundamental proof of the efficacy and safety of hydrogen therapy. More questions, such as the mechanism of action, effective dose, or potential treatment-induced adverse effects, should be addressed by conducting in-depth molecular studies, formal well-designed clinical trials, and comparative studies.

Furthermore, the progress of the oncological treatment of patients within the studies was not discussed in the report. The oxidative stress-induced apoptosis could contribute to the anti-cancer effect of cisplatin and RT, wherefore, the ability to eliminate cancer cells could be suppressed due to the administration of antioxidants like hydrogen molecules. Despite these existing concerns, it would be beneficial to perform further studies on the clinical application of hydrogen as a non-invasive antioxidant therapy to treat hearing loss due to cytotoxic ROS. Animal studies on other forms of hearing loss, such as noise-induced hearing loss and ouabain-induced auditory neuropathy, were previously performed and positive outcomes were observed.13,14

Conclusion: Studies have suggested that both cisplatin and RT could elevate intracellular ROS, and increased oxidative stress is believed to play a major role in cisplatin and RT-induced hearing loss. Thus, it is logical to deduce that reducing the concentration of cytotoxic ROS via antioxidative therapy could potentially reverse the condition and prevent cochlear cell death. Clinical studies, case reports, animal, and preliminary studies have revealed that hydrogen molecules reduce oxidative stress; this, in turn, may have an otoprotective effect against cisplatin or RT-induced hearing loss. Despite cumulative results from previous studies illustrating a potentially promising outcome of hydrogen therapy utilization in the treatment of cisplatin and RT-induced hearing loss, there exists concern regarding the potential disruption of hydrogen therapy on the efficacy of anti-cancer treatments. Moreover, there exists a lack of clarity with respect to practical information such as dosage, time for initiating the treatment, or the most effective route of administration. A well-designed, monitored, randomized clinical trial and comparative studies are required to evaluate the effectiveness, practical utilization of the therapy, and potential interaction with the anti-cancer treatments before its potential application can be realized.

We acknowledge the artist Hiu Ting Law, UK for drawing the figure.