Hyperbaric Oxygen Therapy in Glioblastoma: Current Evidence and Potential Role

Key findings

• HBOT is not a standard stand-alone treatment for glioblastoma. Standard care remains maximal safe resection when feasible, followed by radiotherapy with temozolomide. HBOT is best viewed as an adjunctive or investigational addition, not a replacement for established neuro-oncology treatment ^{1 2 3}.
• The strongest biological rationale for HBOT in glioblastoma is that it may reduce tumour hypoxia, which is linked to resistance to both radiotherapy and chemotherapy ^{1 4 5}.
• The best-established practical use is as a time-sensitive adjunct to radiotherapy or chemoradiotherapy, with HBOT delivered shortly before treatment while tumour oxygenation remains elevated ^{5 6 2}.
• The chemotherapy story is more encouraging than older summaries suggest. The strongest human evidence is not for chemotherapy alone, but for postoperative chemoradiotherapy, including several temozolomide-based glioblastoma regimens. The 2026 meta-analysis reported improved tumour response, improved quality of life, and improved 3-year survival with concurrent HBOT plus chemoradiotherapy ^{7 2}.
• Clinical results remain promising rather than practice-changing. The overall evidence base is still limited by study quality, mixed glioma populations, incomplete survival reporting, and the absence of large international phase 3 trials ^{1 2}.
• In research, HBOT has usually been delivered at approximately 1.8–2.5 ATA, with some studies using up to 2.8 ATA as the upper end of the range, rather than typical practice ^{8 7 2}.
• In modern glioblastoma studies, HBOT has generally been well tolerated, with HBOT-specific side effects mainly ear-related rather than major systemic toxicity ^{8 7 9}.

What Is Hyperbaric Oxygen Therapy?

Hyperbaric oxygen therapy involves breathing near-pure oxygen inside a pressurised chamber, typically at pressures around 2.0 to 2.5 ATA. Under these conditions, oxygen dissolves into the blood plasma at much higher concentrations than under normal atmospheric pressure, which can improve tissue oxygen availability in areas where perfusion is reduced or abnormal ^{1 10}. HBOT protocols in glioblastoma studies most commonly use moderate pressures (around 1.8–2.5 ATA) rather than higher-pressure exposures. ^{8 7 2}

Quick summary

The clearest clinical rationale for HBOT in glioblastoma is as an adjunct to chemoradiotherapy, especially when it is given immediately before radiotherapy. Glioblastoma often contains hypoxic tumour regions, and hypoxic tumour cells are harder to kill with radiation and may also be less responsive to chemotherapy. HBOT can temporarily increase oxygen delivery to tumour tissue, which may improve sensitivity to treatment during that post-HBOT window ^{1 5}.

The newer evidence base is more encouraging than a purely historical reading would suggest. In addition to the older Japanese radiotherapy studies, the 2026 meta-analysis pooled 9 randomized trials involving 837 glioma patients and found that concurrent HBOT was associated with significantly better objective tumour response, better quality of life, and better 3-year overall survival when added to chemoradiotherapy ². That does not make HBOT mainstream standard care, but it does make the adjunctive evidence more substantial and clinically relevant than a simple "preclinical only" summary would imply ^{7 2}.

Care strategy: where HBOT may fit

For newly diagnosed glioblastoma, the priority remains standard treatment: surgery when feasible, followed by radiotherapy with concurrent and adjuvant temozolomide. HBOT should be considered, if at all, as a specialist adjunct that is coordinated with the oncology plan rather than added independently ^{2 3}.

For active tumour treatment, the most defensible place for HBOT is during radiotherapy or chemoradiotherapy, not as a separate wellness intervention. The aim is to improve tumour oxygenation and then treat while that oxygenation effect is still present ^{5 6 2}.

For patients receiving temozolomide-based treatment, the fairest summary is that HBOT now has encouraging human evidence as an adjunct to postoperative chemoradiotherapy, including glioblastoma-heavy populations, but still lacks the level of validation needed for routine adoption across neuro-oncology practice ^{7 2}.

For recurrent disease, the evidence base is smaller, but HBOT has been paired with stereotactic re-irradiation in selected patients with recurrent high-grade glioma, suggesting possible feasibility and disease control in specialist settings ^{9 11}.

Overall, HBOT may be a useful adjunct in carefully selected patients, but it should not delay or replace surgery, radiotherapy, temozolomide, or clinical-trial options ^{2 3}.

Potential role of HBOT in glioblastoma

Improve tumour oxygenation

Glioblastoma is frequently hypoxic, and hypoxia is linked to aggressive tumour biology and treatment resistance. HBOT increases oxygen dissolved in plasma and can raise oxygen tension within tumour and peri-tumoural tissue ^{1 5}. In Beppu et al., direct measurements showed that oxygen pressure in glioblastoma tissue increased significantly under HBOT conditions ⁵.

Increase radiosensitivity

This remains the most clinically established mechanism. Radiation works better in the presence of oxygen because oxygen helps stabilise radiation-induced DNA damage. Several glioma studies were designed around this principle and delivered radiotherapy very shortly after HBOT ^{6 8}. Clinically, this is still the clearest reason HBOT continues to attract interest in glioblastoma.

Support chemotherapy and chemoradiotherapy

Preclinical work showed that hyperoxia could resensitise chemoresistant glioblastoma cells to temozolomide ¹², and later laboratory work suggested that HBOT may enhance sensitivity to temozolomide and radiotherapy while reducing stemness-related behaviour ¹³. However, the evidence no longer stops there.

The strongest human data now support HBOT as an adjunct to postoperative chemoradiotherapy, not just as a theoretical chemotherapy sensitiser. In the 2026 meta-analysis, concurrent HBOT plus chemoradiotherapy was associated with a significantly higher objective response rate and significantly better 3-year overall survival than chemoradiotherapy alone, with improved quality-of-life measures as well ². Importantly, several of the contemporary included trials used temozolomide-based regimens in postoperative glioblastoma patients ^{7 2}.

HBOT has encouraging evidence as an adjunct to chemoradiotherapy, including temozolomide-containing treatment, but the evidence is still less direct for chemotherapy alone in isolation ^{12 2}.

Affect stemness and the hypoxic microenvironment

Hypoxia supports stem-like tumour behaviour, which is associated with resistance and recurrence. Yuen et al. reported that HBOT reduced cancer stem cell formation and enhanced sensitivity to temozolomide and radiotherapy in glioblastoma models ¹³. This remains biologically important, even though it is not the same as proving survival benefit in routine clinical care ^{1 13}.

Why HBOT should not be framed as a stand-alone anti-cancer therapy

HBOT is most credible as an adjunctive strategy. The 2022 scoping review highlighted mixed preclinical findings, including models in which HBOT alone did not behave like a reliable anti-tumour therapy ¹. That is why the current clinical interest is in concurrent HBOT with established oncologic treatment, especially chemoradiotherapy, rather than HBOT monotherapy ^{1 2}.

Key clinical points

During radiotherapy

This remains the clearest clinical setting for HBOT in glioblastoma. The central idea is to oxygenate the tumour and then deliver radiotherapy before that effect fades. In the key studies, radiation was typically delivered within a short period after decompression, often within 15-30 minutes ^{5 6 2}.

Kohshi et al. provided one of the earliest clinically meaningful signals. In that non-randomised malignant glioma study, patients treated with radiotherapy after HBOT had better tumour regression and longer median survival than those treated without HBOT, and outcomes were worse when radiotherapy was delayed beyond 30 minutes after decompression ⁶. That does not prove causality, but it strongly supports the practical importance of timing.

Later phase II studies by Beppu and Ogawa showed that radiotherapy immediately after HBOT could be delivered together with chemotherapy, with encouraging response and survival signals and no major late toxicity signal attributable to the HBOT strategy itself ^{14 15}.

During chemotherapy and chemoradiotherapy

Although the clinical evidence base remains limited, it is no longer accurate to characterize the chemotherapy literature as predominantly preclinical. The strongest human evidence supports HBOT in combination with postoperative chemoradiotherapy, particularly in temozolomide-based glioblastoma treatment regimens ^{7 2}.

The key paper here is Cui et al. 2026. In that meta-analysis of 9 randomized controlled trials involving 837 patients, concurrent HBOT was associated with significantly better objective tumour response than chemoradiotherapy alone, with a pooled odds ratio of 3.67. The response benefit remained significant in sensitivity analysis, and the benefit was seen across both higher- and lower-pressure protocols and across shorter- and longer-session subgroups ².

The same meta-analysis did not show a significant improvement in 1-year overall survival, but it did show a significant improvement in 3-year overall survival, and it also found significantly better Karnofsky performance scores after treatment ². That pattern suggests HBOT may have a more meaningful effect on medium-term disease control and function than on very early survival endpoints.

Mechanistically, this is also coherent. The meta-analysis discussion explicitly links HBOT with reduction of tumour hypoxia, a known contributor to both radioresistance and chemoresistance, and notes the proposed interaction with temozolomide resistance ². Together with the Sun and Yuen studies, this supports a more advanced conclusion: HBOT may not simply support radiation, but may also improve the effectiveness of the broader chemoradiotherapy platform in hypoxic glioma biology ^{12 2}.

The key limitation is that this still does not prove benefit for chemotherapy alone without radiotherapy. Therefore, the patient-facing conclusion should be: HBOT has very encouraging adjunctive evidence in combined chemoradiotherapy, including temozolomide-era glioblastoma treatment, but it is still not proven as an independent chemotherapy enhancer outside that setting ^{12 2}.

In recurrent disease or re-irradiation

In recurrent high-grade glioma, HBOT has been studied as an adjunct to stereotactic re-irradiation. Arpa et al. used HBOT before hypofractionated stereotactic radiotherapy in recurrent high-grade glioma and reported a disease control rate at 3 months of 55.5%, median progression-free survival of 5.2 months, and median overall survival of 10.7 months ⁹.

An older recurrent-glioma study by Kohshi et al. combined HBOT with fractionated stereotactic radiotherapy and reported median overall survival of 11 months in recurrent glioblastoma ¹¹. Taken together, these data suggest a possible salvage role in carefully selected recurrent cases, but the evidence base remains small ^{9 11}.

Clinical Evidence for Hyperbaric Oxygen Therapy in Glioblastoma

Kohshi et al., 1999 provided one of the earliest clinically meaningful signals. In malignant glioma patients, HBOT followed by radiotherapy was associated with better tumour regression and longer median survival than radiation alone, and outcomes were worse when radiotherapy was delayed beyond 30 minutes ⁶.

Beppu et al., 2002 was a mechanistic study rather than a survival trial. Its value is that it directly showed HBOT can increase oxygen pressure inside glioblastoma tissue, which supports the whole logic of post-HBOT treatment timing ⁵.

Beppu et al., 2003 and Ogawa et al., 2006/2012 moved the field into multimodal treatment. These studies showed that radiotherapy could be delivered shortly after HBOT together with chemotherapy, with encouraging clinical outcomes in high-grade glioma and acceptable tolerability in specialist settings ^{14 8 15}. Their limitation is that the regimens were complex and not fully aligned with present-day temozolomide-based standard care.

Yahara et al., 2017 remains one of the more clinically relevant glioblastoma-specific studies because it used a more modern radiotherapy approach with IMRT boosts after HBOT plus chemotherapy. In 24 glioblastoma patients, median overall survival was 22.1 months, 2-year overall survival was 46.5%, and severe non-haematologic toxicity was not observed ⁷.

Arpa et al., 2021 is most relevant for recurrent disease. It suggests HBOT can be paired with short-course stereotactic re-irradiation over 3 to 5 days, with acceptable tolerability and disease control in some patients ⁹.

Cui et al., 2026 now provides the strongest higher-level evidence in the field. In a meta-analysis of 9 randomized trials involving 837 glioma patients, concurrent HBOT with chemoradiotherapy was associated with better objective response, improved quality of life, and better 3-year overall survival ². This materially strengthens the adjunctive case for HBOT, particularly within chemoradiotherapy pathways. At the same time, the paper itself is appropriately cautious: the included studies were all conducted in China, the certainty of evidence was rated low, and only a minority of trials contributed survival data detailed enough for pooling ². So the overall message is very encouraging, but not yet definitive.

How HBOT has been used in research: sessions, pressure, and frequency

There is no single standard HBOT protocol for glioblastoma, but the literature shows consistent patterns ^{1 4}.

In randomized glioma studies, HBOT has typically been delivered at pressures of approximately 1.8 to 2.5 ATA, with most studies clustering within this range. A smaller number of studies used pressures up to 2.8 ATA, but this represents the upper end of published protocols rather than common practice ².

Importantly, subgroup analyses suggest that lower-pressure protocols (below ~2.4 ATA) demonstrate similar treatment effects to higher-pressure protocols, supporting the use of moderate pressures in clinical settings ².

Session duration in these studies has generally ranged from 40 to 90 minutes, most commonly around 60 minutes, with treatment delivered once daily and coordinated with radiotherapy or chemoradiotherapy, typically within 30 minutes after decompression ².

In practical terms, glioblastoma studies have generally used HBOT in one of two ways:

1. Daily on treatment days, particularly during conventional chemoradiotherapy schedules.
2. Before selected boost or salvage fractions, especially in IMRT-based or recurrent stereotactic protocols ^{7 9}.

Safety and Side Effects of HBOT

In current glioblastoma practice, HBOT is used before radiotherapy or chemoradiotherapy and has been reported as well tolerated in modern studies when delivered in specialist settings ^{1 2}.

HBOT-related effects in these studies were mainly ear-related, including earaches and middle-ear barotrauma. In Ogawa et al., 17% of patients developed barotrauma requiring tympanostomy tubes and 12% reported nausea ⁸. Yahara et al. reported earache in 13%, with treatment stopped in 1 patient (4%) ⁷. In Arpa et al., 1 of 9 patients experienced ear pain, with no seizures reported ⁹.

Overall, the safety profile of HBOT in modern glioblastoma studies is favourable, with predominantly mild, manageable side effects and no reported oxygen or pulmonary toxicity ^{8 7 9}.

Frequently Asked Questions

Is HBOT a standard treatment for glioblastoma?

No. HBOT is best described as an adjunctive or investigational therapy in glioblastoma. Standard care remains surgery when feasible, followed by radiotherapy and temozolomide ^{2 3}.

When is HBOT most likely to be useful?

The literature most strongly supports HBOT when it is used shortly before radiotherapy or chemoradiotherapy, because the oxygenation effect is temporary and timing appears important ^{5 6 2}.

Does HBOT support treatment during chemotherapy?

Yes, but the fairest wording is that the evidence is strongest for combined chemoradiotherapy, not chemotherapy alone. The newer randomized evidence and meta-analysis are encouraging, especially for postoperative temozolomide-containing regimens, but HBOT still cannot be described as an established stand-alone chemotherapy enhancer ^{12 2}.

How many HBOT sessions have been used in research?

It depends on the protocol. Some studies used HBOT daily on radiotherapy days over several weeks, while others used HBOT only during a boost phase or during 3-5 days re-irradiation schedules ^{7 9 2}.

What pressures have been used?

Most glioblastoma studies have used HBOT pressures of approximately 1.8–2.5 ATA, with some protocols using up to 2.8 ATA. The higher-pressure range is less commonly used, and current evidence suggests that moderate pressures may achieve similar effects in combination with chemoradiotherapy ^{8 2 10}.

Could HBOT make the tumour grow faster?

There is no clinical evidence from human studies that HBOT accelerates glioblastoma growth. In randomized trials and meta-analysis data, HBOT used alongside chemoradiotherapy is associated with improved tumour response and survival outcomes, with no signal of tumour progression attributable to HBOT. While a single preclinical animal study suggested increased tumour growth with HBOT used alone, this has not been observed in clinical practice, where HBOT is used as an adjunct to standard oncologic treatment.

References