Hyperbaric Oxygen Therapy

Hyperbaric oxygen therapy (HBOT) involves the inhalation of pure oxygen at increased pressure (normally 2-3 atmospheres) [1] [2]. During HBOT you lie on a table in a hyperbaric chamber and breathe oxygen while the pressure is slowly increased. The procedure increases blood oxygen levels and oxygen delivery to tissues independently of hemoglobin [1] [2]. HBOT has a variety of therapeutic applications.

HBOT has been used for centuries to improve conditions related to hypoxia (low oxygen levels in tissues) and ischemia (restricted blood flow) [3]. It is an approved therapy for the treatment of wounds, carbon monoxide poisoning, and soft tissue infections [1]. It is also being researched as a potential therapy in cancer treatment. HBOT promotes angiogenesis (new blood vessel growth), counteracts hypoxia, kills bacteria, and modulates the immune system amongst other effects [2]. Hyperbaric oxygen therapy can increase oxygen levels in cancer cells, which may make them more sensitive to radiotherapy and chemotherapy [4].

Cancer is a highly complex disease process, which encompasses a range of different hallmarks that contribute to cancer initiation and progression [2]. Tumor hypoxia plays a central role in many carcinogenic features and also limits the effectiveness of standard treatments such as radiation, chemotherapy, and immunotherapy [2]. Hypoxia is a critical hallmark of solid tumors and leads to enhanced cell survival, angiogenesis, anaerobic metabolism and metastasis (spread of cancer) [3].

There is growing scientific evidence, which supports the role of HBOT in the inhibition of tumor growth and improving outcomes of standard treatments [2]. It is believed to exert anticancer effects by: (1) limiting cancer-related hypoxia; (2) inducing oxidative stress; (3) and restoring immune function [2] [5]. However, further research is still needed to better understand the effects of hyperbaric oxygen therapy and determine safety and efficacy for different cancer types [5].

History of Hyperbaric Oxygen Therapy

The first documented use of hyperbaric therapy can be traced back to 1662 by a British doctor called Henshaw [2]. He built the first ever hyperbaric chamber and placed patients in the container with pressurized air [2]. However, interestingly, Henshaw’s medical therapy was conducted before there was even a scientific understanding regarding the relationship between pressure and volume of gas (Boyle-Mariotte Law) [2]. It was even prior to the discovery of oxygen gas by John Prestly more than one hundred years later [2].

Progress regarding hyperbaric oxygen therapy in medical treatment was delayed due to the realization of potential negative effects of using 100% concentrations of oxygen by Lavoisier and Seguin in 1798 [2]. In 1872, Paul Bert, considered as the ‘father of hyperbaric of the hyperbaric physiology’, outlined the physiological effects of pressurized air in the human body and also described the potentially neurotoxic effects of oxygen (named the Paul Bert effect) [2]. Lorrain Smith later defined the potential for pure concentrations of oxygen to have a toxic effect on the lungs [2].

Nevertheless, there were also many reports of beneficial effects of increased pressure, and by the late 1800s hyperbaric chambers were used widely for a range of different conditions despite a lack of scientific rationale to explain the therapeutic benefits [6]. These early chambers used decompressed air rather than 100% oxygen due to reports of oxygen toxicity [6]. In 1917, Heinrich Drager explored the use of pressurized oxygen for decompression sickness [7]. His protocols were later adopted and put into practice by Behnke and Shaw in the late 1930s [7].

There was a growing interest in hyperbaric oxygen therapy around the time of World War II for different applications, including for divers who suffered decompression sickness [2]. Research conducted after World War II by the US military brought a much greater understanding of HBOT and survivable pressures [6]. Consequently, the use of HBOT increased during the 1950s and 1960s [6]. It was used to increase the efficacy of radiotherapy, treat anaerobic infections, and carbon monoxide poisoning amongst other applications [6].

However, it was also widely recommended and used for conditions such as arthritis and dementia with little solid scientific basis [6]. As a result, due to concerns around a lack of scientific rigor and regulation, the Undersea & Hyperbaric Medical Society (UHMS) formed _the Committee on Hyperbaric Oxygen Th_erapy in the late 1970s, which is now considered to be the international authority on HBOT [6]. There are currently a plethora of scientific studies on HBOT and many facilities around the world offer the treatment for diverse purposes [6].

Research on Hyperbaric Oxygen Therapy for Cancer

Much early research on hyperbaric oxygen therapy and cancer has focused on concerns that enhanced oxygen and its angiogenic effects could promote tumor growth [3]. However, the scientific consensus today, as demonstrated by preclinical and clinical research, is that HBOT does not have a cancer-promoting effect or enhance recurrence [8]. Rather, it appears to have an inhibitory effect and may reduce cancer growth in certain cancer types (such as breast cancer) [3]. HBOT may also enhance the effectiveness of standard cancer treatments that are limited by hypoxia [1]. However, more well-designed clinical research is still needed to determine the potential role of HBOT in cancer care.

In the scientific literature there are mixed results regarding the effects of HBOT on cancer. There are many experimental and clinical studies that suggest it has no effect on tumors, while there is also a considerable amount of conflicting evidence which suggests that HBOT does have an anticancer effect [1]. Researchers believe that the variety in response to HBOT found in the research is related to the differences in cancer types and also the wide range of different hyperbaric oxygen therapy protocols used [3]. Randomized clinical trials on HBOT as a primary and supportive treatment are still needed with standardized protocols and for specific cancer types [3].

In 2007 a clinical trial was conducted on the use of hyperbaric oxygen to enhance the effects of radiation for high-grade gliomas (brain tumors) [9]. The study included 14 patients with anaplastic astrocytoma (AA) and 11 with glioblastoma multiforme (GBM). The results indicated that HBOT increased survival rates.

A 2009 study involving 6 patients with malignant or brainstem gliomas showed that HBOT prolonged the duration carboplatin (chemotherapy drug) remained in the body [10]. Researchers concluded that HBOT may have the potential to enhance the clinical antitumor effects of chemotherapy.

In 2008 a study was published on the effect of hyperbaric oxygen therapy and radiotherapy on quality of life in 21 patients with mouth and throat cancer [11]. Xerostomia (dry mouth) and other related problems commonly occur when major salivary glands are damaged by radiation. HBOT significantly reduced swallowing-related problems, increased saliva quantity, and improved sense of taste. Researchers concluded that HBOT had a positive effect on patient quality of life by reducing radiotherapy-related side effects.

A 2012 review of the literature on hyperbaric oxygen and cancer outlines numerous preclinical (laboratory and animal) studies that show HBOT has a significant inhibitory effect as a standalone treatment against certain types of breast cancer [3]. Despite positive findings no clinical trials have been conducted on HBOT as a primary treatment for breast cancer in humans. Researchers called for further research and investigation into the potential anticancer effects of HBOT.

The same review article also summarized numerous studies on HBOT and colon cancer [3]. The researchers found that HBOT as a stand alone treatment did not have any effect for colorectal cancer, but showed potential as an adjuvant therapy to enhance the efficacy of other cancer treatments such as photodynamic therapy and chemotherapy.

Overall, there is not currently enough clinical evidence to determine if HBOT could be an effective primary or supportive treatment for cancer in humans. However, preliminary research suggests it may have a potential therapeutic role for certain cancer types. It may also enhance the efficacy and reduce side effects of other cancer treatments, which may in turn improve outcomes and quality of life for cancer patients.

Potential Applications of Hyperbaric Oxygen Therapy

Hyperbaric oxygen therapy involves the application of pure oxygen at a pressure higher than 1 atmosphere (atm) [1]. However, most HBO treatments are carried out at a pressure of 2 to 3 atm [1]. The increased pressure within a hyperbaric chamber combined with the inhalation of 100% oxygen significantly increases the amount of bioavailable oxygen dissolved in the blood plasma [1].

There are three main factors that constitute the therapeutic basis for hyperbaric oxygen therapy: (1) Breathing 100% oxygen saturates the lungs with oxygen, which creates a positive gradient and favors diffusion of oxygen to hypoxic tissues; (2) with the high pressure oxygen concentration in the blood raises (amount of dissolved gas is directly proportional to its partial pressure); (3) and the high pressure decreases the size of oxygen gas bubbles [2]. In other words, HBOT significantly increases oxygen supply to the blood and to the tissues even without the involvement of hemoglobin (which normally binds and transports oxygen) [2].

The short-term effects of increased oxygenation include enhanced oxygen delivery to ischemic tissues (lacking blood flow), vasoconstriction (constriction of blood vessels), reduction of edema (swelling), and modulation of the immune system [1]. Long-term effects include neovascularization (growth of new blood vessels) and stimulation of collagen production [1].

The effects of HBOT can be harnessed to correct low oxygen levels in tissues (hypoxia) and low blood oxygen levels (hypoxemia). It can help to clinically manage a range of different conditions such as:

1. Air or gas embolism (blocked artery from air bubble)
2. Decompression sickness
3. Acute burn injuries
4. Gas gangrene (lethal soft tissue infection)
5. Carbon monoxide poisoning
6. Compromised grafts
7. Traumatic ischemia (impaired blood flow and hypoxia from injury)
8. Delayed radiation injuries
9. Wound healing
10. Brain abscesses
11. Soft tissue infections
12. Bone infections
13. Severe anemia

Hypoxia can provide health benefits under certain circumstances, for example intermittent exposures [2]. However, chronic hypoxia generally creates pathological stress for cells and is linked to the onset and progression of many diseases [2]. Counteracting hypoxia is therefore a powerful therapeutic intervention.

Pathological hypoxia affects both cancer cells and the tumor microenvironment [5]. It plays an important role in the process of cancer progression and spread of disease [5]. In fact, hypoxia enhances certain aggressive features of cancer such as cell survival, angiogenesis (new blood vessel growth), and metastasis (spread of cancer) [5]. It also regulates tumor metabolism and immune cell function [5]. Furthermore, hypoxia minimizes the efficacy of conventional treatments such as chemotherapy, radiotherapy, and immunotherapy [5].

Hypoxia signifies increased tumor progression and aggressiveness, which in turn hampers patient survival [5]. Therefore some cancer patients may potentially benefit from treatments that target hypoxia such as hyperbaric oxygen therapy [5].Accumulating evidence indicates that hyperoxic treatments (which increase blood oxygen levels) inhibit tumor growth and help to enhance the efficacy of other cancer treatments [5].

It is believed that the primary anticancer effects of hyperbaric oxygen therapy are related to three potential mechanisms of action [5]:

1. Reversal of tumor hypoxia
2. Generation of reactive oxygen species (oxidative stress)
3. Restoring immune function

Research into hyperbaric oxygen therapy and cancer shows that it could potentially provide therapeutic benefits for a variety of malignancies, including breast cancer, prostate cancer, head and neck cancer, colorectal cancer, leukemia, brain tumors, cervical cancer and bladder cancer [2] [12]. The main potential applications of HBOT for cancer could be as part of a comprehensive treatment program, as an adjuvant to chemotherapy, or an adjuvant to radiotherapy [2].

However, the use of HBOT for cancer is not currently an approved indication [2]. Overcoming tumor hypoxia is a major problem that still needs to be solved in cancer treatment and HBOT shows potential in this regard. However, even at high pressures, tumor hypoxia can not be fully resolved with HBOT alone [2]. Therefore, the efficacy of HBOT is limited and may only have therapeutic potential as an adjuvant or supportive therapy in cancer care [2].

Risks and Side Effects of Hyperbaric Oxygen Therapy

Hyperbaric oxygen therapy is normally a well tolerated treatment with an acceptable rate of complications [12]. However, as with all medical procedures, there are certain associated risks. The two most common side effects of HBOT are related to high levels of oxygen (oxygen toxicity) or high atmospheric pressure (barotrauma) [12].

Potential symptoms or side effects after hyperbaric oxygen therapy can include fatigue and lightheadedness [13]. More severe potential side effects include [13]:

• Lung damage
• Fluid build up or rupture of the middle ear
• Sinus damage
• Changes to vision (causing nearsightedness or shortsightedness)
• Oxygen poisoning (leading to lung failure, fluid in the lungs or seizures)

However, side effects from HBOT are generally only mild and temporary provided treatment does not last longer than 2 hours and the pressure of the chamber is not above 3 atmospheres [13].