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Hyperbaric oxygen: The Basics

Typical protocols for hyperbaric oxygen therapy (HBOT) have patients breathe 100% pure oxygen under pressure between 1.5 and 2.5 ATA (atmospheres absolute). 

Oxygen is transported in blood to tissues by two different mechanisms: combined with hemoglobin in red blood cells as well as dissolved in the plasma. Under normal conditions, 97 % of the inhaled oxygen is boung to hemoglobin whereas plasma typically contains only 0.32 % dissolved oxygen (around 3% of the inhaled oxygen). At a pressure of 3 atm, the amount of plasma oxygen increases from 0.32 vol% (at 1 atm) to 6 vol%.

HBOT dramatically increases the amount of dissolved oxygen in the blood and therefore enhances tissue oxygenation.

Hyperbaric treatment has other beneficial biochemical and cellular effects, such as reduction in edema, constriction of blood vessels and activation of phagocytosis. 

The major site of utilization of oxygen within the average cell is the mitochondria, which accounts for about 80% of cellular oxygen use. Consequenty, Hyperoxygenation can ensure better mitochondrial oxygen utilization and the mitochondria is thought to be key to Hyperbaric oxygen's potential anti-cancer effects. 

Cancer and Oxygen: 

One of the major challenges in the treatment of cancer is the occurrence of local hypoxia (low oxygen) within the central tumour areas. The application of HBOT may help overcome the problem of oxygen deficiency in the poorly oxygenated areas of neoplastic tissue.

Poor perfusion inside the tumour mass limit the action of cytostatic agents, as they reach distant tumour cells in lower concentrations and decreased efficiency of radiotherapy. 

Cancers exhibit a dysregulated metabolism characterized by lactate fermentation (lactic acid production) despite the presence of oxygen, a phenomenon known as the Warburg effect whereas normal cells only use these pathways in the absence of oxygen. Lactate production has a strong dependency on glucose and both of these correlate strongly with aggressive capacity and invasive potential of a cancer. Metabolic cancer therapies exploit these phenomena.

For instance, the ketogenic diet's anti-cancer effects are largely attributed to a reduction in the glycolytic substrates (less substrate to be utilized for lactate production) and insulin signaling while healthy cells readily adapt to ketones as an efficient energy substrate, many cancers are not able to make this adaptation.  

Cellular energy metabolism is closely linked to the extent of oxygenation of a tissue. Under normal conditions when oxygen is readily available, cells produce up to 90 percent of their ATP by oxygen dependent mitochondrial respiration. When oxygen is limited, cells convert to using anaerobic fermentation to preserve ATP production and sustains cellular function and promotes survival in the face of hypoxia (largely driven by the transcription factor HIF-1).

HIF-1 enhances the expression of over 60 genes, many involved in angiogenesis, growth, and survival. With regards to angiogenesis, immature and leaky blood vessels are created which are unable to adequately perfuse the entire tumor which further leads to the formation of hypoxic regions inside the tumor.

Tumor hypoxia is also known to mediate some chemoresistance and radioresistance. Because these therapies work in part by stimulating the reactive oxygen species, reduced oxygen availability lessens their efficacy.

Hyperbaric oxygen therapy can oxygenate hypoxic tumor regions. "HBOT has been shown to inhibit angiogenesis and tumor growth and increase survival time as a stand-alone or adjuvant therapy to standard care in a variety of cell, animal, and human studies²"

The ketogenic diet, ketone supplementation, and HBOT target overlapping metabolic pathways which are especially prominent in metastatic cells. 

"The current state of knowledge almost unequivocally states that HBO is not only unconducive to further cancer development, but even might reduce the main tumour mass¹

Preliminary data

Kawasoe (2009): "Hyperbaric oxygen clearly enhanced the chemotherapeutic effects of carboplatin on both tumor growth and lung metastasis in osteosarcoma-bearing mice⁹"

Wei (2018) "When performed together with Melatonin, HBOT effectively inhibited tumorigenicity of gastric cancer through selectively inducing a robust tumor suppressive apoptosis response.¹⁰"

Sletta (2017) In a breast cancer model, "HBOT significantly suppressed tumor growth in both the triple positive and negative tumors.^13"

Xie (2018) "The concentration of oxygen in a glioma tumor was improved and the antitumor rate was increased when Temozolomide was combined with Hyperbaric Oxygen.²⁶"

Yue (2017) "Hyperbaric oxygen combined with radioactive seed implantation could slow [esophageal] tumor growth and increase survival time of tumor bearing mice.²⁷" 

basic human data

In a 2019 study, forty-four non small cell lung cancer patients with distant metastasis received metabolically supported chemotherapy "MSCT" (administration of chemotherapy regimen following induced hypoglycemia) plus ketogenic diet, hyperthermia and HBOT combination. 

MSCT involves a 12-h fasting starting the previous evening and the administration of pharmaceutical doses of regular insulin prior to the administration of chemotherapy to cause an acute metabolic stress on cancer cells as well as to increase the efficacy of chemotherapeutic drugs by increasing membrane permeability. Chamber was used produce 1.5 ATA pressures. 

The study included patients with relatively unfavorable characteristics: majority had impaired performance status, all had distant metastasis, around 40% had brain metastasis. Despite this poor patient profile, the response and survival rates seem encouraging when compared to previous studies.

HBOT and hyperthermia was given the same day or the next day sequentially after chemotherapy.

Overall response rate was 61.4%. Mean overall survival and progression-free survival was 42.9 months and 41.0 months respectively²². 

In a 2017 case report, a 29-year-old woman with stage IV (T4N3M1) triple-negative invasive ductal carcinoma of the breast received MSCT. In October 2016, and a whole body (18F)-fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET-CT) scan revealed a 77 mm x 55 mm primary tumor in her left breast, multiple left pectoral and axillary lymph nodes, multiple widespread liver masses, and an upper left nodular abdominal lesion. 

A follow-up whole body 18F-FDG PET-CT scan in February 2017 showed a complete therapeutic response with no evidence of abnormal FDG uptake. 

The authors conclude "this single case study presents evidence of a complete clinical, radiological, and pathological response following a six-month treatment period using a combination of MSCT and a novel metabolic therapy in a patient with stage IV Triple Negative Breast Cancer.²³"

In a 2020 study, 25 patients with metastatic pancreatic ductal carcinoma (stage IV) who received MSCT (either gemcitabine-based or FOLFIRINOX regimen administered concomitantly with induced hypoglycemia) plus ketogenic diet, hyperthermia, and HBOT combination.

Median overall survival and median progression-free survival were 15.8 months and 12.9 months. In a large randomized trial comparing FOLFIRINOX and gemcitabine in patients with metastatic pancreas cancer, the median overall survival was 11.1 months and 6.8 months in the FOLFIRINOX group and gemcitabine group, respectively so MSCT clearly provides a survival advantage²⁴. 

Twenty-two patients with NSCLC with multiple pulmonary metastases intravenously received paclitaxel and carboplatin and yperthermia of the whole thoracic region was also administered weekly during intravenous infusion of carboplatin in all patients. In addition, 16 (72%) of 22 patients received hyperbaric oxygen treatment immediately after weekly chemotherapy.

The median time to progression of disease in all patients was 8 months and in 16 patients with HBO was 9 months indicating a benefit from the inclusion of HBO²⁵.

Radiation & Chemotherapy

UHMS indication #11 for Hyperbaric Oxygen is "Delayed Radiation Injury (Soft Tissue and Bony Necrosis)³"

Hyperbaric Oxygen is well known with regards to delayed radiation injuries and is frequently used for this purpose in the hospital setting. The management of delayed radiation injury, especially when bone necrosis is present, still requires multi-disciplinary management.

Hyperbaric oxygen has been applied as a therapy for delayed radiation injury for more than 30 years. Surveys have shown that at most hyperbaric centers in the U.S., nearly 50% of patients receiving hyperbaric oxygen are being treated for radiation injury.

Radiation injuries are classified as acute, sub-acute or delayed. Acute injuries are usually self-limited, and are treated symptomatically.Sub-acute injuries are typically identifiable in a few organ systems, for example radiation pneumonitis following the treatment of lung cancer has an onset typically 2 to 3 months after completion of irradiation. These are generally self-limited but occasionally evolve to become delayed injuries. Some sub-acute injuries may persist for several months. Delayed radiation complications are typically seen after a latent period of six months or more and may develop many years after the radiation exposure.

Because a central cause of radiation injury is vascular obliteration, the effect of hyperbaric oxygen in stimulating angiogenesis is an important mechanism whereby hyperbaric oxygen is effective in radiation injury. Hyperbaric oxygen also reduces fibrosis and is likely to mobilize and stimulate an increase of stem cells within irradiated tissues. 

Some human studies demonstrating the benefit of HBO in radiation induced injury: 

176 patients with refractory radiation-induced hemorrhagic cystitis were studied with HBOT - After an average on 37 sessions, 89.8% of patients showed resolution of hematuria¹¹.  

57 women treated with HBOT for late radiation-induced tissue toxicity (LRITT) related to breast cancer found "patient-reported outcomes were positive and improvements were observed. HBOT was a well-tolerated treatment for LRITT and its side-effects were both minimal and reversible¹². 

16 patients with soft-tissue wounds without signs of healing after salvage surgery, after radiation, and most after chemotherapy were treated with hyperbaric oxygen therapy. "The healing processes seemed to be initiated and accelerated by HBO2. Fourteen of the 16 patients healed completely.¹⁴"

HBO is not used in the early postradiation period as it may potentiate the effects of radiation. Some authors do not start HBO therapy until 2 months after the last radiotherapy treatment (Hart and Strauss 1986)20. 

Review of a cumulative 14-year experience with 124 patients with various radiation tissue damage (Osteoradionecrosis 39%, proctitis 10%, cystitis 8%, anterior chest wall radiation necrosis 6%, all other soft tissue radiation damage including head and neck, problem wounds, compromised flaps and grafts, optic neuropathy, brain/spinal cord, abdominal wall and vaginal vault damage 36%) has shown that HBO therapy led to significant improvement in 94% of the cases¹⁹

According to Jain (2017) HBOT is used in: Osteoradionecrosis of the Jaw, Mandible, Chest wall, Vertebrae, Radiation Myelitis, Delayed Radiation Injuries of the Extremeties, Head and Neck, Larynx, Abdomen and Pelvis, Bladder and Proctitis²⁰. 

There is some data supporting the use of Hyperbaric Oxygen in conjuction with radiation as hypoxic tumors are often radiation resistant. Human studies showed an additive effect in lung and cervical cancer but not bladder⁴. 

A review looking at published and unpublished data identified 4805 patients with squamous cell carcinoma of the head and neck treated in 32 randomized clinical trials (9 studies of which were specifically with HBO) found "overall hypoxic modification of radiotherapy in head and neck cancer did result in a significant improved therapeutic benefit." Furthermore, "the risk of distant metastases was not significantly influenced although it appears to be less in the tumours treated with hypoxic modification.⁵"

There is some data to suggest synergy between HBO and Chemotherapy. However "a promising chemotherapy adjuvant, although its observed effectiveness depends strongly upon the cytotoxic agent and the experimental conditions under which is it measured, as well as the type of the tumour⁴." Some data suggests enhanced effects of 5-FU as well as carboplatin and mild hyperthermia."

In summary, it's dramatically clear that HBOT can help healing from radiation or surgical damage but it appears that formal suggestions on safely combining HBO with chemotherapy or radiation might be premature because current robust clinical data not appear to currently exist.

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Can hbot worsen cancer?

There is some concern that HBO may promote cancer growth or recurrence but it appears that this is unwarranted. 

In a survey of this topic, majority of the hyperbaric practitioners who responded did not consider
HBO to have cancer-promoting or cancer-accelerating properties.¹⁵ 

In a review by Feldmeier (2003) done for the UHMS, called Hyperbaric oxygen: does it promote growth or recurrence of malignancy, which reviewed the published literature from clinical reports, animal studies and cell culture studies. Feldmeier et al stated "In vitro, in vivo and clinical studies strongly suggest no more than a neutral effect of HBO2 on tumor growth. In fact some studies suggest a negative impact of HBO2 on malignant progression or formation." Furthermore, "In conclusion, the published literature on tumor angiogenesis mechanisms and other possible mechanisms of cancer causation or accelerated growth provides little basis for HBO2 to enhance malignant growth or metastases. A history of malignancy should not be considered a contraindication for HBO2 therapy.¹⁷"

A 2012 review by Moen, called Hyperbaric Oxygen Therapy and Cancer--A Review, stated "we summarized the work performed on HBO and cancer in the period 2004-2012 which looked at available information accrued after the Feldmeier review. Based on the present as well as previous reviews, there is no evidence indicating that HBO neither acts as a stimulator of tumor growth nor as an enhancer of recurrence. On the other hand, there is evidence that implies that HBO might have tumor-inhibitory effects in certain cancer subtypes¹⁶"

In a review by Daruwalla (2006) they state "most of the literature indicates that HBO has no impact on tumor growth—be it stimulatory or inhibitory," that is, a seemingly neutral effect on its own¹⁸. " Despite theoretical considerations of tumor stimulation, to date there is enough evidence to preclude any tumor stimulatory effects of HBO.¹⁸ Moreover, "HBO does not overtly contribute to increased tumor growth, nor is it effective as a stand-alone treatment."

It makes the most sense to use Hyperbaric therapy sparingly however as a synergist with other metabolic therapies rather than a standalone. One approach is to pair HBO with a metabolic IV therapy such as IV Alpha Lipoic Acid which is usually administered 2-3x weekly or to pair oral dosing of metabolic treatments with Hyperbaric therapy. This notion is supported by Daruwalla "studies that combined HBO with other therapies were more successful in achieving tumor control¹⁸".

Anti-Cancer Mechanisms¹⁸:

Tumor cells adapt to hypoxic environments by Glycolytic shift where tumor cells preferentially switch to aerobic glycolysis. HBO greatly improves oxygen perfusion in tumors, thus altering the hypoxic microenvironment and promoting normal Krebs cycle activity and oxidative phosphorylation. 

The most potent stimulus for angiogenesis is metabolic stress induced during hypoxia (hypoxia is a potent stimulator of VEGF via HIF 1 and HIF 2). Reoxygenation of hypoxic cells induces degradation of HIF-1 and subsequent VEGF production and angiogenesis in vitro.

HBO may increase intratumoral ROS levels past the threshold and induce tumor cell destruction, hence the synergistic action with other pro-oxidative therapies like wormwood derivatives or IV Vitamin C.

Tumors possess cellular mechanisms (particularly active under hypoxic conditions) that allow them to evade apoptosis despite the extent of DNA damage therefore negating hypoxia with Hyperbaric oxygenation is key to hedging these anti-apopototic mechanisms.  

Metabolic Therapies

A few therapies we work with are synergistic with Hyperbaric Oxygen, we call these "metabolic therapies" or "the metabolic approach."

The aberrant signaling that drives tumor angiogenesis creates immature and leaky blood vessels which are unable to adequately perfuse the entire tumor. This leads to the formation of hypoxic regions and upregulates HIF-1.  HIF-1 enhances the expression of over 60 genes, many involved in glycolysis and fermentation, angiogenesis, growth, and survival. Hyperbaric Oxygen down-regulates the transcriptional protein HIF-1. 

Cancer metabolism is characterized by lactate fermentation in the presence of oxygen, a phenomenon known as the Warburg effect. 

Glucose dependency and lactate production, two key features of the Warburg effect, correlate strongly with aggressive capacity and invasive potential. 

The anti-cancer effects of the Ketogenic Diet are largely attributed to a reduction in the glycolytic substrates and insulin signaling which fuel cancer metabolism. 

The expression of ketone utilization enzymes is often reduced in malignant cancers compared to their normal tissue counterparts. 

The ketogenic diet, ketone supplementation, and HBOT target overlapping metabolic pathways which are especially prominent in metastatic cells. 

Poff and D’Agostino (2013) studied the VM-M3 mouse model of metastatic cancer to compare tumor progression and survival in mice fed a standard diet or Ketogenic diet with or without Hyperbaric Oxygen delivered atm 2.5 ATA for 90 min three times weekly. 

The ketogenic diet alone significantly decreased tumor growth, and increased mean survival time by 56.7% in mice with systemic metastatic cancer. Hyperbaric Oxygen alone did not influence cancer progression, combining the Ketogenic diet with Hyperbaric Oxygen elicited a significant decrease in tumor growth rate, with a 77.9% increase in mean survival time.²¹

Most Alternative metabolic therapies work to restore normal energy production pathways.

ALA (Alpha Lipoic Acid), HCA (hydroxycitric acid) and ketosis synergize with Hyperbaric Therapy. 

The Mitochondrial Rescue protocol popularized by Dr. Neil Mckinney also adds B1, Acetyl-L-Carnitine, Niacinamide and Metformin

Intense Aerobic exercise can also be helpful.

In our experience, Metabolic cancer therapies are the strongest available Alternative Cancer Therapies.

Although as in all therapies, not all patients respond to this approach, however, for those that do, the results can be dramatic.

Ketogenic & HBOT

IV vitamin c & hbot

In "Pharmacological Ascorbic acid and Hyperbaric Oxygen Therapy Target Tumor Cell metabolism via an Oxidative Stress Mechanism" Dr. Dominic D’Agostino and his group conducted experiments with regards to IV Vitamin C and Hyperbaric Oxygen Therapy.

They set out to "evaluate AA-induced oxidative stress, and to investigate AA’s synergy with
another non-toxic, pro-oxidative metabolic therapy: Hyperbaric Oxygen (HBOT)." Ascorbic Acid or "AA" is in reference to Vitamin C. 

These experiments used mouse VM-M3 Cells which are highly metastatic cells taken from a spontaneous brain tumor in inbred mice. Cells were treated with a less than cytotoxic concentration of Vitamin C(<0.5mM) and one session of HBOT (100% O2 for 60 minutes at 2.5 ATA). Sub-cytotoxic concentrations (<0.5mM) were used as doses higher than this are already cytotoxic on their own. 

24 hour treatment with HBOT and 0.3mM Vitamin C had significantly enhanced cytotoxicity compared to all other treatments. 

The group concluded "Pharmacological AA shows an anticancer effect in vitro and exhibits cytotoxicity through an oxidative stress mechanism that is therapeutically exploited by HBOT" and "our findings indicate that these non-toxic, pro-oxidative metabolic therapies should be further investigated as adjuvants to the current standard of care."

In the article "Increasing the Effectiveness of Intravenous Vitamin C as an Anticancer Agent⁷" one group has published "We propose the utilization of hyperbaric oxygen immediate­ly after IV vitamin C therapy to increase its effectiveness as an anticancer agent, in order to increase the formation of hydrogen per­oxide, and therefore enhance the anticancer effect of IV vitamin C."

Dr. Paul Anderson ND has lectured on his experience combining Hyperbaric Oxygen and various Alternative IV therapies including IV Vitamin C⁸.  

"For three years at the hospital and outpatient center we have run High Dose IV Vitamin-C (HDIVC) with HBOT on the same day. In all those administrations we have had few to no complaints of adverse effects." 

Paul Anderson ND HBOT IVC Protocols

The typical protocol is HBOT dive then HDIVC administration.

• Low dose Vitamin C (under 25 grams) pair with HBOT from 1.3 to 2.5 ATA 

• High dose strategies (over 25 grams) should be paired with 1.3 to 1.5 ATA. 

IVc & HBOT

Questions about Hyperbaric Chambers?

Call Us 780-757-8378