Clinical Efficacy of Hydrogen Therapy on Acute Radiation Enteritis and Inflammatory Response in Patients with Cervical Cancer Undergoing Concurrent Chemoradiation Therapy

Abstract

Purpose

Acute radiation enteritis (ARE) is a common toxic inflammatory reaction in patients with cervical cancer undergoing concurrent chemoradiation therapy (CCRT). Molecular hydrogen, as a novel antioxidant and anti-inflammatory agent, may alleviate treatment-related toxicity. This study aimed to evaluate the efficacy of inhaled hydrogen in preventing ARE and modulating systemic inflammation.

Methods

Eligible patients with cervical cancer undergoing CCRT were prospectively enrolled and randomized into an experimental group (n = 28) or a control group (n = 30). The experimental group received inhalation therapy with a hydrogen-oxygen gas mixture (66.6% hydrogen, 33.3% oxygen; 3 L/min, 2 h/d) on each radiation therapy day. Inflammatory biomarkers—including C-reactive protein, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and interleukin 6—as well as hemogram parameters, fecal occult blood, Late Effects Normal Tissue Task Force—Subjective, Objective, Management, and Analytic scores; Patient-Generated Subjective Global Assessment scores; and Radiation Therapy Oncology Group enteritis grades were monitored during treatment and Response Evaluation Criteria in Solid Tumors scores.

Results

Baseline characteristics (age, tumor stage, pathology, and surgical history) were balanced between groups (P > .05). Compared with the control group, the experimental group showed significantly lower levels of C-reactive protein, neutrophil-to-lymphocyte ratio, interleukin 6, and fecal occult blood positivity rates (P < .05). Clinical assessments also indicated lower Late Effects Normal Tissue Task Force–Subjective, Objective, Management, and Analytic and Patient-Generated Subjective Global Assessment scores and milder Radiation Therapy Oncology Group enteritis grading in the hydrogen group (P < .05). Importantly, no significant difference in tumor response was observed between groups based on the Response Evaluation Criteria in Solid Tumors, suggesting that hydrogen therapy did not interfere with the antitumor efficacy of CCRT. No adverse events related to hydrogen inhalation were reported.

Conclusion

Hydrogen inhalation is a safe and effective adjunctive therapy that significantly alleviates inflammation and mitigates clinical symptoms of ARE in patients with cervical cancer who are undergoing CCRT, without compromising antitumor treatment outcomes.

Introduction

Cervical cancer is the fourth most common cancer among women worldwide and ranks as one of the leading causes of cancer-related deaths.¹ Concurrent chemoradiation therapy (CCRT) is widely recognized as the standard of care for patients with locally advanced cervical cancer. Compared with radiation therapy (RT) alone, CCRT can significantly improve 5-year overall survival and progression-free survival rates by 10% to 15%.² Despite its efficacy, CCRT is frequently associated with severe treatment-related toxicities, notably acute radiation enteritis (ARE), a consequence of radiation-induced intestinal mucosal injury. The incidence of ARE can be as high as 60% to 80%, with symptoms such as diarrhea, abdominal pain, and rectal bleeding.³ These symptoms not only have a severe impact on patients’ quality of life (QoL) but can also result in treatment interruptions.⁴ The underlying pathophysiology of ARE is multifactorial, involving oxidative stress, inflammatory signaling pathways, and microvascular injury, all contributing to intestinal mucosal damage.⁵ Current preventive strategies encompass dietary modifications, probiotic administration, and the utilization of anti-inflammatory agents.⁶ However, the effectiveness of these therapies is limited, and they often come with severe side effects such as immunosuppression and gastrointestinal discomfort.^6,7 Therefore, there is a compelling need to develop novel therapeutic approaches that can effectively prevent or alleviate ARE without compromising the antitumor efficacy of CCRT.^7,8

Recently, hydrogen therapy has emerged as a promising anti-inflammatory and antioxidant intervention owing to its unique biological properties.⁹ Hydrogen is a natural, effective reactive oxygen species (ROS) scavenger and anti-inflammatory agent, and ROS are key contributors to oxidative stress and tissue damage in ARE.^10,11 Preclinical investigations have demonstrated that hydrogen can attenuate oxidative stress and inflammation in various tissues, including the gastrointestinal tract, by modulating cytokine expression and promoting tissue repair.¹⁰ Previous studies have also demonstrated that hydrogen-rich water can significantly reduce radiation-induced intestinal damage in rats and lower the levels of pro-inflammatory cytokines compared to controls.¹² Furthermore, another study indicated that inhaling hydrogen could reduce oxidative stress and apoptosis in mouse lung tissue, thereby alleviating radiation-induced lung injury.¹³ Although clinical data on hydrogen therapy in the context of radiation enteritis are still limited, its high safety profile has been confirmed in multiple studies. High-concentration hydrogen therapy is well-tolerated and has been recommended as an adjunctive treatment for patients with COVID-19.^9,14 These findings collectively suggest that hydrogen therapy represents a safe and potentially effective strategy for the prevention and management of ARE in patients with cervical cancer receiving CCRT.

Key clinical and inflammatory biomarkers have emerged as crucial indicators of systemic inflammatory responses and prognostic outcomes in cancer patients. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) reflect the balance between tumor-associated inflammation and antitumor immune surveillance and have been shown to be valuable tools for monitoring treatment response and disease progression.¹⁵ Numerous studies have demonstrated that elevated NLR and PLR values are significantly associated with poor prognosis and suboptimal treatment response in patients with cervical cancer.¹⁶ Additionally, these markers are positively correlated with the incidence of ARE.^17,18 Interleukin-6 (IL-6), a pro-inflammatory cytokine, plays a key role in the inflammatory cascade.¹⁹ Persistently elevated IL-6 levels indicate a chronic inflammatory state, which not only promotes tumor progression but also exacerbates damage to normal tissues during treatment, thereby increasing the risk of severe complications such as ARE.²⁰ During CCRT in patients with cervical cancer, intestinal injury may lead to insufficient nutritional intake, malabsorption, and weight loss.²¹ The Patient-Generated Subjective Global Assessment (PG-SGA) is a validated tool for evaluating nutritional status in oncology patients. It incorporates parameters such as weight change, dietary intake, gastrointestinal symptoms (eg, diarrhea, rectal bleeding, and abdominal pain), functional capacity, and metabolic stress.²² Higher PG-SGA scores reflect poor nutritional status and are independently associated with diminished treatment tolerance and an elevated risk of ARE in patients with cervical cancer.^23,24

Given the unique anti-inflammatory and antioxidant properties of hydrogen, this prospective clinical study aimed to systematically evaluate its therapeutic potential in the prevention and mitigation of ARE. Specifically, the study investigated the impact of hydrogen inhalation on inflammatory biomarkers (NLR, PLR, and IL-6), nutritional status (PG-SGA sores), patient-reported gastrointestinal symptoms, and overall QoL in patients with cervical cancer undergoing CCRT.

Methods and Materials

Object of research

This prospective study enrolled patients with a pathologic diagnosis of cervical cancer who received CCRT at the oncology department of Hospital A between February 2023 and December 2023. Inclusion criteria were as follows: (1) pathologic confirmation of cervical cancer (including squamous cell carcinoma, adenocarcinoma, and adenosquamous carcinoma) with indications for CCRT as per the National Comprehensive Cancer Network Cervical Cancer Guidelines²⁵; (2) aged between 18 and 75 years; (3) no evidence of tumor metastasis, other malignancies, a history of inflammatory gastrointestinal diseases, or gastrointestinal surgeries; and (4) an Eastern Cooperative Oncology Group performance status score of 0 to 2. Exclusion criteria included (1) patients with mental disorders that hinder treatment compliance; (2) patients with active infectious diseases; (3) pregnant or lactating women; (4) patients who could not tolerate the disease or nonexperimental interventions, leading to withdrawal from treatment; and (5) patients who refused to continue participation or withdrew from the study for personal reasons. Participants were randomly assigned to either the experimental group (n = 28) or the control group (n = 30) using a random number table. This study was approved by the Ethics Committee of Hospital A (Approval No. 20240101; Date: October 15, 2024). All participants provided written informed consent before enrollment.

Regimen of concurrent CCRT

All patients in this study received concurrent CCRT. The chemotherapy regimen followed the recommendations of the National Comprehensive Cancer Network Cervical Cancer Guidelines (2023 version 1) and the Chinese Society of Clinical Oncology Cervical Cancer Treatment Guidelines (2023).^25,26 Patients with squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma received a chemotherapy regimen consisting of taxanes and platinum-based agents: paclitaxel 135 to 175 mg/m² on day 1 and cisplatin 50 mg/m² on days 1 to 2, administered every 3 weeks. Each treatment cycle was 3 weeks, with the number of cycles determined based on the patient’s disease stage and surgical situation.

For the RT regimen, patients who required adjuvant treatment after surgery (with a vaginal margin distance > 0.5 cm) received pelvic external beam RT using intensity modulated RT, with a dose of 45 to 50 Gy in 25 fractions (5 days per week, with weekends off), over a period of 5 weeks. Patients who did not undergo surgery or had a vaginal margin distance ≤ 0.5 cm after surgery received intracavitary brachytherapy, with a dose of 6 Gy per fraction, administered in 5 sessions. Patients with positive pelvic or abdominal lymph nodes could receive an additional 10 to 15 Gy.

Methods

The experimental group received concurrent hydrogen inhalation therapy from days 1 to 25 of RT. Specifically, on each RT day, patients inhaled a hydrogen-oxygen gas mixture (66.6% hydrogen and 33.3% oxygen by volume) via a nasal cannula either before or after RT, with each session lasting for 2 hours at a flow rate of 3 L/min. The hydrogen-oxygen gas mixture was prepared using a hydrogen-oxygen nebulizer, with purified water as the source material, by electrolyzing water to generate the gas. This solution was administered 5 times per week, totaling 25 sessions, on the same days as external beam RT. The hydrogen-oxygen gas mixture was prepared using the AMS-H-03 hydrogen-oxygen nebulizer, manufactured by Shanghai Asclepius Meditech Co, Ltd. The control group did not receive any additional gas inhalation during RT.

According to the Radiation Therapy Oncology Group (RTOG)/European Organization for Research and Treatment of Cancer criteria, patients who developed grade 2 radiation enteritis were treated with “montmorillonite powder, 1 sachet 3 times daily” or “loperamide, 2 capsules initially, followed by 1 capsule after each episode of diarrhea.”²⁷ Supportive care, such as fluid replacement, electrolyte correction, and parenteral nutrition, was provided when necessary.²⁷

Evaluation indicators

During RT, samples were regularly sent to the laboratory of Hospital A for testing relevant indicators. Testing was conducted on days 0, 5, 10, 15, 20, and 25 of RT. The tests included estimation of hemoglobin levels, platelet counts, neutrophil counts, lymphocyte counts, C-reactive protein (CRP) levels, IL-6 levels, and presence of fecal occult blood. On days 0, 5, 10, 15, 20, and 25 of RT, the Late Effects Normal Tissue Task Force—Subjective, Objective, Management, Analytic (LENT-SOMA) scale²⁸ and the PG-SGA scale were used to assess radiation injury and nutritional status. The LENT-SOMA scale is used to evaluate late adverse effects on normal tissues after RT, covering subjective, objective, management, and analytic aspects, and helps to identify and quantify the severity of potential late adverse reactions. The PG-SGA scale, through patient self-report and health care professional assessment, comprehensively evaluates nutritional status, with scores ranging from well-nourished to severely malnourished. Patients scoring ≥ 9 require urgent symptom management and/or nutritional intervention.

On day 25 of RT, the RTOG acute radiation injury grading system was used to assess intestinal reactions, categorized as grade 0 (no significant discomfort), grade 1 (increased bowel movements or altered bowel habits without medication), grade 2 (diarrhea and pain requiring symptomatic treatment), grade 3 (abdominal distension with intestinal dilation on radiograph, requiring parenteral nutrition), and grade 4 (intestinal obstruction, perforation, fistula, or significant bleeding requiring transfusion). The severity of acute enteritis was compared between the 2 groups. On day 25 of RT, the Response Evaluation Criteria in Solid Tumors (RECIST) was used to assess tumor response. The RECIST criteria classify tumor response into complete response (CR, disappearance of all target lesions), partial response (PR, at least a 30% decrease in the sum of diameters of target lesions), stable disease (no significant change in the sum of diameters of target lesions), and progressive disease (PD, at least a 20% increase in the sum of diameters of target lesions or the appearance of new lesions). The treatment responses of the 2 groups were compared to evaluate the effectiveness of hydrogen therapy for tumor control.

Statistical analysis

Statistical analysis was performed using SPSS version 25.0 (IBM Corp). Continuous variables with normal distribution were expressed as the mean ± standard deviation (mean ± SD) and compared between groups using the independent samples t-test. For non-normally distributed data, the Wilcoxon rank-sum test was applied. Categorical variables were presented as frequency and percentage (n, %) and compared using the χ² test; Fisher’s exact test was used when the expected frequency (T ≤ 1) or sample size (n < 40) was insufficient. To assess the effects of time, group, and their interaction on repeated measurements during RT, generalized estimating equations were used. All statistical tests were 2-tailed, and P values < .05 were considered statistically significant.

Results

Baseline characteristics and safety profile

A total of 66 patients were initially enrolled. After accounting for attrition, 28 patients in the experimental group and 30 in the control group were included in the final analysis. There were no statistically significant differences between the 2 groups in terms of age, body mass index (kg/m²), tumor stage, diameter, histologic type, or surgical history, as presented in Table 1, indicating baseline comparability. Routine blood tests showed similar trends in both groups, with no additional hematologic toxicity observed in the hydrogen group, as presented in Table E1, supporting the safety of hydrogen therapy. Throughout the treatment, no hydrogen-related adverse effects were observed, confirming the safety of hydrogen-oxygen inhalation therapy. Common side effects such as abdominal pain, diarrhea, and nausea were managed symptomatically.

Table 1.

Baseline characteristics of experimental and control groups

Characteristic		Experimental group (n = 28)	Control group (n = 30)	t/x2 value	P value
Age, y (n [%])	<60	21 (75.0)	23 (76.7)	0.02	.88
	≥60	7 (25.0)	7 (23.3)
BMI kg/m2 (n [%])	<23.9	17 (60.7)	20 (66.7)	0.22	.63
	≥23.9	11 (39.3)	10 (33.3)
FIGO2018 stages	II	10 (35.7)	13 (43.3)	0.49	.78
	III	18 (64.3)	17 (56.7)
Tumor diameter (cm)		4.56 ± 1.55	3.95 ± 1.15	1.69	.095
Pathologic differentiation (n [%])	Well	5 (17.9)	0 (0.0)	8.09	.064
	Moderately	15 (53.6)	24 (80.0)
	Poorly	8 (28.5)	6 (20.0)
Pathology (n [%])	Squamous cell carcinoma	24 (85.7)	25 (83.3)	0.06	.8
	Adenocarcinoma	4 (14.3)	5 (16.7)
Surgery (n [%])	No	21 (75.0)	20 (66.7)	0.48	.48
	Yes	7 (25.0)	10 (33.3)

Abbreviations: BMI = body mass index; FIGO 2018 = International Federation of Gynecology and Obstetrics 2018.

Hydrogen therapy attenuates inflammatory responses and radiation-induced intestinal injury

Radiation-induced inflammatory responses play a pivotal role in the pathogenesis of ARE. In this study, a comprehensive panel of biomarkers—including CRP, IL-6, NLR, PLR, fecal occult blood positivity, LENT-SOMA, PG-SGA, and RTOG scores—was used to assess inflammatory responses and radiation-induced intestinal injury.

CRP: A systemic inflammation marker

CRP, a sensitive acute-phase reactant, serves as a reliable marker of systemic inflammation.²⁹ As presented in Fig. 1A, CRP levels progressively increased in both groups over the course of RT; however, patients receiving hydrogen therapy demonstrated significantly lower CRP concentrations beginning on day 15. Specifically, the mean CRP level on day 15 was 10.02 ± 4.12 mg/L in the hydrogen group, compared with 15.63 ± 3.39 mg/L in the control group (P = .0002). This disparity further widened on day 20 (13.32 ± 4.04 vs 21.26 ± 5.69 mg/L, P < .0001) and day 25 (14.45 ± 5.01 vs 26.77 ± 10.73 mg/L, P < .0001), highlighting the potent anti-inflammatory effect of hydrogen therapy in mitigating RT-induced systemic inflammation.

Figure 1.

Changes in inflammatory biomarkers and clinical assessment scores between the experimental and control groups during radiation therapy. (A) C-reactive protein (CRP) levels, (B) neutrophil-to-lymphocyte ratio (NLR), (C) platelet-to-lymphocyte ratio (PLR), (D) interleukin-6 (IL-6) levels, (E) Patient-generated subjective global assessment (PG-SGA) scores, and (F) Late effects normal tissue task force – subjective, objective, management, analytic (LENT-SOMA) scores. The data are presented as the mean ± SD. Statistical significance between groups was analyzed at each time point. *P < .05, **P < .01, ***P < .001, ****P < .0001.

NLR and PLR: Composite hematologic inflammation markers

NLR is a widely recognized marker of systemic inflammation, reflecting the dynamic balance between innate immune activation (neutrophils) and adaptive immune competence (lymphocytes).¹⁶ As shown in Fig. 1B, NLR values increased progressively during RT in both groups, consistent with radiation-induced inflammatory stress. In the experimental group, however, the degree of increase was significantly mitigated. From days 0 to 15, no significant intergroup differences were observed (all P > .05). By day 20, NLR levels in the hydrogen group were significantly lower than those in the control group (8.03 ± 1.05 vs 9.40 ± 1.86, P = .0362), and this difference was further accentuated at day 25 (8.80 ± 1.44 vs 10.97 ± 2.96, P < .0001). These findings suggest that hydrogen inhalation effectively attenuated the systemic inflammatory burden induced by CCRT.

PLR is another hematologic inflammatory marker associated with immune dysregulation and endothelial activation.¹⁶ As depicted in Fig. 1C, PLR values also showed an upward trend throughout treatment in both groups. Although the experimental group consistently exhibited lower PLR values at each time point, the differences did not reach statistical significance. On day 25, the PLR value was 339.77 ± 81.62 in the hydrogen group versus 392.10 ± 94.11 in the control group (P = .0501). The overall intergroup comparison across all timepoints approached statistical significance (P = .0511), suggesting a possible modulatory effect of hydrogen therapy on platelet-related inflammatory activity.

IL-6: A key cytokine in ARE

IL-6 is a key pro-inflammatory cytokine implicated in radiation-induced tissue damage and mucosal barrier disruption.¹⁹ As shown in Fig. 1D, IL-6 levels remained relatively stable in the hydrogen group but showed a marked increase in the control group during RT. At baseline (day 0), there was no significant difference between the 2 groups (5.11 ± 2.94 pg/mL vs 4.56 ± 1.15 pg/mL, P = .9904). Although mild fluctuations were observed at days 5 to 15, the intergroup differences were not statistically significant (all P > .05). Notably, by day 20, IL-6 levels were significantly elevated in the control group compared with the hydrogen group (9.21 ± 5.19 vs 6.16 ± 1.29 pg/mL, P = .0037). This disparity became more pronounced at day 25, with the control group exhibiting markedly higher IL-6 concentrations (12.59 ± 5.77 vs 5.83 ± 3.68 pg/mL, P < .0001). The overall trend analysis confirmed a significant group effect (P < .0001), demonstrating that hydrogen inhalation suppressed radiation-induced upregulation of IL-6 levels and systemic cytokine release.

Fecal occult blood positivity: Indicator of intestinal mucosa integrity

Fecal occult blood positivity serves as a noninvasive indicator of radiation-induced intestinal mucosal injury and microbleeding,³⁰ correlating with the severity of ARE. As summarized in Table 2, fecal occult blood positivity increased over time in both groups; however, the hydrogen group consistently demonstrated a lower proportion of positive cases. At baseline (day 0), no significant difference was observed between groups. By day 5, the hydrogen group showed a significantly lower positivity rate (10.71% vs 30.00%, P = .0375), suggesting early mucosal protection. Significant intergroup divergence was observed at day 20 (32.14% vs 60.00%, P = .009) and day 25 (42.86% vs 66.67%, P = .016). Cumulative analysis over the RT course showed a significant reduction in fecal occult blood positivity in the hydrogen group (χ² = 16.278, P < .001), reinforcing its protective effect on intestinal mucosa integrity.

Table 2.

Fecal occult blood positivity (%, n) during radiation therapy (RT) in experimental and control groups

RT period	Experimental group (n = 28)	Control group (n = 30)	χ2 value	P value
Day 0	17.86% (5)	23.33% (7)	0.613	.43369
Day 5	10.71% (3)	30.00% (9)	4.327	.0375
Day 10	42.86% (12)	56.67% (17)	2.486	.11488
Day 15	39.29% (11)	43.33% (13)	0.569	.451
Day 20	32.14% (9)	60.00% (18)	6.842	.009
Day 25	42.86% (12)	66.67% (20)	5.784	.016
Intergroup comparison			16.278	0

Notes: “ns” indicates nonsignificant differences between groups.

LENT-SOMA score: Integrated evaluation of radiation-induced intestinal toxicity

The LENT-SOMA scoring system provides a validated, clinician-assessed measure of gastrointestinal toxicity, especially suited to evaluating radiation-induced intestinal injury.²⁸ As shown in Fig. 1E, both groups exhibited progressive increases in LENT-SOMA scores during RT; however, patients receiving hydrogen therapy demonstrated significantly milder symptom progression. At baseline (day 0), LENT-SOMA scores were comparable between the 2 groups. From days 5 to 10, although scores increased in both groups, intergroup differences remained nonsignificant (P > .05). By day 15, the experimental group maintained a significantly lower score (0.42 ± 0.21) compared with the control group (0.55 ± 0.30, P = .0332), with the disparity persisting at day 20 (0.39 ± 0.21 vs 0.53 ± 0.22, P = .0308). At the end of RT (day 25), the difference was most pronounced: 0.33 ± 0.16 in the hydrogen group versus 0.60 ± 0.16 in the control group (P < .0001). Overall longitudinal analysis confirmed that hydrogen therapy significantly attenuated the progression of radiation-induced intestinal toxicity (P < .0001).

PG-SGA: Nutritional impact of ARE

The PG-SGA score is a tool for evaluating nutritional status and symptoms affecting food intake, widely used in oncology supportive care.²² As illustrated in Fig. 1F, PG-SGA scores increased steadily in both groups, reflecting progressive nutritional deterioration; however, this trend was substantially mitigated in the hydrogen group. At baseline, there was no significant difference between groups (0.60 ± 0.62 vs 0.43 ± 0.50, P = .975). From days 5 to 10, scores in the control group rose sharply, reaching 5.93 ± 0.72 by day 10, significantly higher than the hydrogen group (2.83 ± 0.75, P < .0001). The divergence widened further at day 15 (6.79 ± 0.79 vs 3.10 ± 0.76), day 20 (6.07 ± 0.86 vs 3.07 ± 0.79), and day 25 (5.50 ± 1.45 vs 3.83 ± 1.29), with all comparisons achieving P < .0001. This consistent difference confirms that hydrogen therapy effectively preserved patients’ nutritional status and alleviated gastrointestinal symptoms associated with ARE.

RTOG toxicity grading: Overall clinical enteritis severity

The RTOG criteria were used to grade the severity of ARE based on clinician-observed gastrointestinal toxicities.²⁷ As shown in Table 3, the majority of patients in the hydrogen therapy group exhibited only grade 0 to 1 toxicity. Specifically, by the end of RT, 64.29% of patients in the experimental group experienced grade 1 toxicity, compared with only 30.00% in the control group. Conversely, grade 2 toxicity was significantly more prevalent in the control group (63.33%) versus the experimental group (28.57%). Higher-grade toxicities (grade 3) were rare in both groups but occurred more frequently in the control group (6.67% vs 3.57%). Statistical analysis revealed a significant intergroup difference (χ² = 9.516, P = .023), indicating that hydrogen inhalation effectively reduced the severity of radiation-induced gastrointestinal damage.

Table 3.

Radiation Therapy Oncology Group (RTOG) scores at different radiation therapy (RT) days in experimental and control groups

RT period	Experimental group (n = 28)	Control group (n = 30)	χ2 value	P value
Grade 0	3 (10.71%)	0 (0.00%)
Grade 1	18 (64.29%)	9 (30.00%)
Grade 2	8 (28.57%)	19 (63.33%)
Grade 3	1 (3.57%)	2 (6.67%)
Intergroup comparison			9.516	.023

Tumor response remains unaffected by hydrogen inhalation

A crucial concern in supportive therapies is whether they interfere with the therapeutic efficacy of RT and chemotherapy.³¹ In this study, tumor response was assessed using the RECIST evaluation criteria, providing a standardized measure of radiologic response to therapy. As summarized in Table 4, the CR rate was comparable between the experimental group (71.43%) and the control group (80.00%). The PR occurred in 17.86% and 10.00% of patients, respectively. The stable disease and PD were infrequent in both groups (stable disease, 3.57% vs 0.00%; PD, 7.14% vs 10.00%). Importantly, no statistically significant difference in overall tumor response distribution was observed (χ² = 1.997, P = .573), demonstrating that hydrogen therapy did not compromise the antitumor efficacy of concurrent CCRT. This finding underscores the oncologic safety of hydrogen inhalation as an adjunctive supportive treatment.

Table 4.

Response Evaluation Criteria in Solid Tumors (RECIST) scores at different radiation therapy (RT) days in experimental and control groups

RT period	Experimental group (n = 28)	Control group (n = 30)	χ2 value	P value
Complete response	20 (71.43%)	24 (80.00%)
Partial response	5 (17.86%)	3 (10.00%)
Stable disease	1 (3.57%)	0 (0.00%)
Progressive disease	2 (7.14%)	3 (10.00%)
Intergroup comparison			1.997	.573

Discussion

ARE is a frequent and debilitating complication in patients with cervical cancer undergoing RT, primarily resulting from direct radiation-induced injury to the intestinal mucosa and subsequent activation of inflammatory pathways.⁴ Concurrent chemotherapy can exacerbate mucosal damage induced by RT by further enhancing inflammatory responses and inhibiting repair mechanisms.³²

Such adverse effects not only compromise patients’ QoL but may also necessitate treatment interruptions, ultimately diminishing the overall therapeutic efficacy. Molecular hydrogen has demonstrated a unique capacity to selectively scavenge cytotoxic ROS, particularly hydroxyl radicals and peroxynitrite, which are potent mediators of oxidative tissue damage.¹³ Additionally, hydrogen gas can exert anti-inflammatory effects by inhibiting inflammatory signaling pathways, such as nuclear factor κ B and inducible nitric oxide synthase, thereby reducing the release of pro-inflammatory factors.¹² Previous studies have confirmed the protective role of hydrogen in various acute and chronic inflammatory conditions, with a favorable safety profile that supports its clinical translation.^10,14 This study aimed to verify the potential efficacy of hydrogen gas in preventing and treating ARE in patients with cervical cancer.

Although no significant differences were observed in levels of hemoglobin, neutrophils, platelets, and lymphocytes between the experimental and control groups during treatment, a marked decline in these indicators was noted over the course of treatment in both groups. This decline is consistent with the myelosuppressive effects of RT, indicating that the impact of RT and chemotherapy on bone marrow hematopoiesis is inevitable.³³ However, the observed improvements in inflammatory and nutritional biomarkers in the hydrogen-treated group provide preliminary evidence supporting its therapeutic potential. CRP, a classical acute-phase reactant, was significantly lower in the experimental group compared with the control group. This reduction may be attributed to the anti-inflammatory effects of hydrogen, which potentially limits the systemic release of pro-inflammatory mediators—a finding consistent with prior experimental research.³⁴ Nevertheless, although reduction of CRP levels may reflect a dampened inflammatory state, its direct correlation with long-term clinical outcomes remains to be elucidated and warrants further investigation.

NLR and PLR are 2 inflammatory markers that have been extensively studied in recent years in the context of tumors and inflammatory diseases.¹⁶ These indices not only reflect systemic inflammatory status but are also closely associated with clinical prognosis and treatment response.¹⁷ RT and chemotherapy suppress bone marrow hematopoiesis, particularly affecting lymphocytes, although neutrophils have higher resistance to radiation.^35,36 In parallel, the inflammatory response induced by RT and chemotherapy may further elevate neutrophil levels, thereby increasing NLR values.³⁷ In this study, NLR values in the experimental group were significantly lower than those in the control group (P < .05), suggesting that hydrogen therapy may attenuate systemic inflammation by modulating neutrophil proportions.^38,39 Although the PLR values in the experimental group showed a trend toward being lower than those in the control group, this difference was not statistically significant (P > .05), which may be related to sample size or the sensitivity of PLR values as an inflammatory marker.⁴⁰ Because a pivotal pro-inflammatory cytokine, IL-6, plays a central role in mediating acute-phase responses and inflammation.¹⁹ This study found that IL-6 levels did not significantly increase in the experimental group after treatment, although they significantly increased in the control group (P value < .05). This suggests that hydrogen therapy may suppress IL-6 release or interfere with upstream regulatory pathways such as nuclear factor κ B and signal transducer and activator of transcription 3, thereby reducing systemic inflammation.⁴¹

The LENT-SOMA scoring system encompasses clinical symptoms and functional assessments, making it suitable for a comprehensive evaluation of post-RT toxicity. Fecal occult blood positivity has been positively correlated with ARE severity and is often accompanied by higher LENT-SOMA scores and more advanced RTOG grades.^30,42 A higher fecal occult blood positivity rate is generally associated with higher LENT-SOMA scores and more severe RTOG grading.²⁸ The experimental group exhibited significantly lower rates of fecal occult blood positivity and LENT-SOMA scores compared with the control group (P value < .05), suggesting that hydrogen may protect the intestinal mucosa, reduce local hemorrhage, and mitigate ARE severity. The PG-SGA score is used to identify the risk and severity of malnutrition in patients with cancer.²² Radiation-induced gastrointestinal symptoms—such as anorexia, diarrhea, and abdominal pain—often lead to weight loss and deteriorating nutritional status, as reflected in elevated PG-SGA scores. In the present study, PG-SGA scores were significantly lower in the hydrogen-treated group (P < .05), indicating better nutritional status. This may be attributed to the reduction in gastrointestinal symptoms resulting from hydrogen’s protective effects on the intestinal tract.²⁴ Good nutritional status not only enhances the patient’s QoL but may also improve treatment adherence and outcomes. Importantly, although hydrogen possesses strong antioxidant properties, no significant differences in tumor response, as assessed using RECIST criteria, were observed between the 2 groups (P > .05). This indicates that while hydrogen selectively scavenges excess free radicals, it does not interfere with the important mechanism of RT and chemotherapy, which involves the production of ROS to kill tumor cells.^7,13 This highlights the clinical feasibility of hydrogen as an adjunctive treatment that mitigates toxicity and improves patient tolerance without compromising antitumor efficacy.

Nevertheless, this study has several limitations. The relatively small sample size and short follow-up duration may limit the generalizability of the results. Future studies should incorporate larger, multicenter cohorts with extended follow-up to improve the robustness and external validity of the findings. Additionally, interindividual variability, differences in treatment adherence, and lifestyle factors may have confounded the observed outcomes. Subsequent research should aim to control for these potential confounders to ensure more accurate and reliable conclusions.

Conclusion

In summary, this study demonstrated that hydrogen inhalation therapy, when administered concurrently with CCRT, significantly attenuates radiation-induced inflammatory responses and intestinal injury in cervical cancer patients, without compromising antitumor efficacy. The favorable safety profile and anti-inflammatory effects of hydrogen suggest its potential as a supportive strategy in the management of acute radiation enteritis. Further studies with larger sample sizes and extended follow-up are warranted to validate these findings and to explore the long-term clinical benefits and mechanisms of hydrogen therapy in oncologic settings.