A narrative review of adjuvant therapy for glioma:hyperbaric oxygen therapy

Tao Xue ,Jia-Sheng Ding ,Bing Li ,De-Mao Cao ,Gang Chen

1 Department of Neurosurgery ＆ Brain and Nerve Research Laboratory,The First Affiliated Hospital of Soochow University,Suzhou,Jiangsu Province,China

2 Department of Neurosurgery,Yancheng City No.1 People’s Hospital,The Fourth Affiliated Hospital of Nantong University,Yancheng,Jiangsu Province,China

3 Department of Neurosurgery,The Affiliated Hospital of Yangzhou University,Yangzhou,Jiangsu Province,China

Abstract Glioma is a kind of common malignant tumor in neurosurgery and has a high mortality and morbidity rate,which poses a serious threat to the health of people all over the world.Surgery is the preferred treatment for patients with glioma,radiotherapy or chemotherapy can be used after surgery.Although there are clear therapeutic protocols,the efficacy and safety of these protocols are clinically proven,a large number of patients are still dissatisfied with the treatment and the health of the patient remains unsatisfactory.Therefore,it is crucial to look for other treatments or complementary treatments.In the modern medical treatment,hyperbaric oxygen (HBO) therapy is widely used in various kinds of pathological state of adjuvant therapy,and existing studies confirm the efficacy of HBO therapy in combination with surgery,radiotherapy,chemotherapy,and photodynamic therapy.Studies have shown that HBO can inhibit the growth of tumor tissue as an adjunctive therapy.This provides novel insights into the clinical treatment of glioma patients.Although HBO is not licensed for use in cancer treatment,as a kind of adjuvant therapy,the treatment effect of HBO can be accepted by the patients and its cost lower,which could be regarded as an ideal safe treatment.

Key words:adjuvant therapy; central nervous system; chemotherapy; glioma; hyperbaric oxygen therapy; hypoxic; radiotherapy; temozolomide

INTRODUCTION

The main diseases of the central nervous system can be classified into two categories:brain tumors and cerebrovascular diseases.Both of them have extremely high mortality and disability.1Cerebrovascular disease can mainly be divided into hemorrhagic stroke and ischemic stroke.Hemorrhagic stroke accounted for about 20% of all strokes,2and ischemic stroke accounted for 80%.3,4Gliomas account for 40-50%of the central nervous system tumor.Glioma is a malignant tumor originating from intracranial neutral glial cells.As an aggressive and fatal malignancy,the growth of glioma causes diffuse recombination of brain functional networks.5Among them,glioblastoma was the most aggressive and malignant.6Despite significant advances have achieved in multi-modality therapy for glioma,the overall prognosis of glioma patients remains poor.7,8The standard treatment strategy for gliomas is surgery plus chemotherapy or radiation.9Even so,the prognosis was poor,with an average survival time of less than 15 months.10In addition,the side effects of radiotherapy or chemotherapy are obvious and the related costs are relatively expensive,so it is particularly important to find a better treatment or adjuvant treatment.

Hyperbaric oxygen (HBO) has become an adjunct therapy for a variety of diseases and is suitable for a variety of medical conditions.11It is worth mentioning that HBO therapy has been unanimously approved in the treatment of chronic radiation injuries.As is known to all,hypoxia plays an important role in the development of cerebrovascular disease.12,13With the further study of the tumor,hypoxia of tumor tissue has become a recognized fact.14And hypoxia promotes the growth of tumor tissue.15,16Numerous studies have demonstrated that HBO can improve the efficacy of radiotherapy or chemotherapy in glioma patients combined with radiotherapy or chemotherapy(such as temozolomide (TMZ)).17,18Existing study has shown that performing radiotherapy immediately after HBO with chemotherapy was safe with virtually no late toxicity for highgrade gliomas.19This treatment strategy may be promising and merits further investigation.Clinically,glioma patients may have partial nerve function defects after operation.Therefore,patients need HBO for postoperative rehabilitation and can also amplify the effects of radiotherapy or chemotherapy.

Therefore,this paper comprehensively describes the application of HBO therapy as an adjuvant therapy for other therapeutic schemes in the treatment of glioma,so as to provide a sound decision for clinical treatment.In this review,literature searches were performed on PubMed,and articles that were published until August 2020 were included.

THE COMPATIBILITY OF HYPERBARIC OXYGEN THERAPY WITH MAINSTREAM TREATMENTS

HBO therapy and chemotherapy

As an oral imidazolidazinone methylator,TMZ can inactivate the DNA repair enzyme O6-alkylguanine-DNA alkyltransferase and is the preferred chemotherapy drug for the clinical treatment of glioma.20TMZ improves survival in glioma patients and prolongs progression-free survival after surgical treatment.9However,due to the toxicity of TMZ,its therapeutic dose is limited.21Because of the high degree of malignancy of gliomas,the 5-year survival rate under current standard treatment is still less than 8%.22Therefore,it is urgent to improve the traditional chemotherapy drugs for glioma.Hypoxia may be one of the reasons why glioma is resistant to TMZ.17Modern medical science generally believes that hypoxia is conducive to tumor growth,and can promote the formation of blood vessels in tumor tissues,and improve tumor invasiveness.23A relevant study has shown that the increase of lactic acid is closely related to the poor prognosis of glioma.24HBO therapy is expected to overcome hypoxia in the hypoxic region of tumor tissue.Studies have shown that HBO therapy alone does not inhibit tumor growth,while TMZ combined with HBO significantly inhibits tumor growth (Table 1).

Two mechanisms have been proposed for TMZ combined with HBO therapy.On the one hand,tumor tissue hypoxia tends to decrease after HBO treatment,and some hypoxic areas return to normal oxygen supply,while the increase of oxygen concentration in tumor tissue makes tumor tissue more sensitive to chemotherapy drugs.28On the other hand,HBO may enhance the cell cycle arrest effect of chemotherapeutic drugs.TMZ alkylates guanine in genomic DNA at position O6 inducing impaired DNA repair and G2/M arrest.29When TMZ is used to treat glioma cells,the number of cells blocked in G2/M phase is:hypoxia (18%),normal oxygen (27%) and hyperbaric oxygen (23%).Therefore,it can be concluded that HBO therapy can enhance the affinity of tumor cells to TMZ.25Study has shown that inflammation plays an important role in the development of tumors,which mainly through a variety of inflammatory factors.When Nimustine was used in combination with HBO,it was found that the expression of many inflammatory factors was reduced and the growth of tumor tissue was inhibited.Therefore,HBO therapy also played an important role in inhibiting the inflammatory response (Table 1).

Table 1:The effect of HBO on glioma

HBO therapy and radiotherapy

Radiotherapy utilizes the so-called classical oxygen effect in tumor treatment.Under radiation,water molecules break down to form hydrogen ions and hydroxyl groups,the hydrogen ions react with oxygen,forming highly stable hydrogen peroxide and hydroxyl radicals,which damages the DNA chain,causing cell death.It follows that the effect of radiotherapy is closely related to the oxygen content in tumor tissue.It was observed that mice breathing pure 1 atmosphere absolute (1 atmosphere absolute = 101.325 kPa) oxygen required a one-third smaller dose of X-rays than mice that were breathing air to achieve similar cancer regression.30HBO combined with radiotherapy may have two functions:one is to enhance the effect of radiotherapy as a sensitizer.Second,it can reduce the damage of delayed radiotherapy as a therapeutic agent.31,32The incorporation of HBO and radiotherapy can reduce tumor growth,improve tumor local control and prolong survival time.33It is obvious that the lack of oxygen in tumor tissues is caused from insufficient blood flow.It is generally accepted that there are two mechanisms of radiation resistance due to hypoxia:limited diffusion and chronic hypoxia.This is mainly due to the oxygen is hard to reaching the distal vessels of the tumor and the transient vascular obstruction caused by acute hypoxia.34It is well known that the Radio-sensitivity of tumors is determined by the partial pressure level of oxygen and can be significantly increased in the presence of small amounts of oxygen.11Due to low oxygen consumption and low blood flow,the internal oxygen partial pressure of glioma decrease relatively slow after decompression.We hypothesized that concentration ofoxygen in the tumor after decompression can still maintain a period of time.According to this hypothesis,HBO combined radiotherapy can increase the sensitivity of tumor tissue for radio-therapy,and would not damage normal brain tissue,which can be concluded that this novel combination therapy can be very effective for the glioma patients treatment.35

CONCLUSION AND PROSPECT

To sum up,as a kind of auxiliary treatment,HBO therapy for glioma has the advantages of safety,cheap and effective,but its mechanism and possible side effects has not yet been fully elucidated,which requires more basic research to study the exact molecular mechanism,and a lot of clinical cases for retrospective study were also needed.HBO therapy has not yet been approved for clinical use.However,we believe that HBO therapy will certainly enter the clinic as a safe and reliable treatment in the near future.

Author contributions

Manuscript writing:TX; manuscript revision:JSD,BL; manuscript drafting:DMC,GC.All the authors read and approved the final version of the manuscript for publication.

Conflicts of interest

The authors have no conflicts of interests to declare.

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None.

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Peer review

Externally peer reviewed.

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