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Hyperbaric Oxygen Therapy for
Cancer Treatment Side Effects

NEW DIRECTIONS IN CANCER RESEARCH
My current work focuses on research in cancer and aging. The cancer research is concentrated on metabolic approaches to treatment, applying therapies that interfere with the metabolism of cancer cells.

Cancer pH manipulation: lab studies. In 2007, I performed an initial study at Wake Forest University using a cocktail of drugs that was found to inhibit the ability of cancer cells to utilize glucose.

Two years ago, I performed a second study at the University of Miami on cancer glucose metabolism. In that research, I looked at two types of cancers, neuroblastoma and breast cancer, which both rely heavily on glucose. In fact, most types of cancer thrive on glucose and increase glucose uptake as they become more aggressive. The more aggressive the cancer cells, the faster the rate of glycolysis and the more lactic acid they produce. If the lactic acid is not expelled, the cells become so acidic they self-destruct. Seven different mechanisms have been identified through which cancer cells over-express the acid they produce.

For the first phase of this study, I selected two medications, drugs that are known to block two of the mechanisms responsible for pumping out lactic acid. I bathed the cancer cells in those drugs. Within 24 hours, 30% of the cancer cells died. That 30% cell death correlated with the accumulation of acid inside the malignant cells. I realized that if we blocked the efflux of acid from the cancer, the cells would succumb to their own acid production.

Taking this process a step further, I placed the remaining live cancer cells in a high-sugar medium, which included the two drugs blocking the efflux of acid. The hypothesis was that the more glucose the cancer cells consumed, the more acid they would produce. In 24 hours we saw 50% cell death in those remaining cells, and once again, cell death correlated with an increasing accumulation of acid in the cancer cells.

Cancer pH manipulation: initial clinical results. Based on those findings, we began clinical trials overseas, working with cancer patients who had far-advanced stage IV cancers. Our goal was to determine to what degree this metabolic approach was effective in vivo, in the human body. From those trials, we confirmed that the therapy was nontoxic and gained invaluable information on dosage.

Once I had those results, I treated our first patient in the United States. M.N. had been diagnosed with metastatic endometrial carcinoma, stage IV. A debulking procedure had been performed to remove tumor tissue, but it was not possible to remove all of the tumor invading bowel and bladder. She was offered chemotherapy but declined. The oncologist indicated that she had perhaps a year to live and that she would probably become painfully symptomatic within six months. She decided to begin metabolic therapy. I developed a therapeutic cocktail that targeted four of the pumps that expel acid from cancer cells. After eight weeks, her tumor markers normalized, and she has been in complete remission from stage IV cancer for 21 months. That success generated a great deal of excitement, and I began treating other patients.

At that point, I was put in touch with a cancer researcher at Harvard, Dr. Vikas Sukhatme, MD, PhD, who told me that he had been lecturing on these same concepts for three years. He became a colleague with whom I began collaboration. In our research, we found that some patients had a tremendous response to this approach, but others did not respond. A third type of response was temporarily favorable and then the cancer would seem to find an escape path.

Cancers that thrive on amino acids. To carry this research further, I have been targeting protein scavenging cancers. It is well published in the literature that amino acids also feed cancer. Many cancers not only thrive on glucose from carbohydrates but become highly aggressive when excess glutamine, methionine, or phenylalanine are available. Glutamine, for example, can be used by cancer cells to directly create nucleosides that provide the basis for DNA.

This holds implications for clinicians. Many nutritionists and naturopaths replete cancer patients with glutamine to support immune function. However, it is important to bear in mind that numerous cancers are fueled by glutamine. Every cancer patient must be treated individually. The advanced-stage cancer patient's needs are highly specific, because completely different processes are in play.

A three-pronged approach to metabolic therapy. Our current strategy is to develop a comprehensive regimen in the metabolic treatment of cancer. In this approach, we block three of the metabolic pathways in the cancer cell: (1) the efflux of lactic acid, (2) glutamine use, and (3) the pentose phosphate pathway (an alternative to glycolysis).
Applying this protocol, we see patients on an ongoing basis and are collecting case reports in collaboration with Dr. Sukhatme from Harvard. The next step is a clinical trial. I believe that this cancer cocktail approach, like the HIV cocktail, is one of the most promising methods of cancer treatment today. I have developed a pharmaceutical company to design cancer cocktails that will be delivered by nanotechnology. The cocktail is placed in a nanoparticle and tagged so that it is only taken up by cancer cells. To date, we have completed the nanoparticle, costed out the particle, and demonstrated its financial viability. The next step is clinical trials in an animal model and then human clinical trials.

Normally, it can take up to seven years to obtain FDA approval for a drug. On the other hand, if a medication is approved as an "orphan drug" (one that treats rare conditions with fewer than 250,000 or 300,000 cases per year), the FDA will allow the drug to be fast-tracked within two to three years. The first condition we study will probably be pancreatic cancer or glioblastoma, because the prevalence of cases would qualify the medication as an "orphan drug."

CURRENT CLINICAL STRATEGIES
We look at cancer from a number of perspectives. The popular belief is that patients develop cancer because they are immune compromised. The reality is more complex. In aggressive forms of cancer, malignant cells send self-protective signals to the patient's white blood cells and bone marrow. This prompts white blood cells to secrete factors that support angiogenesis, enabling the cancer to create more blood vessels and continue to grow. In immunotherapy, our goal is to stimulate the immune system to destroy the cancer cells, through comprehensive treatment using a metabolic approach, immunology, and diet therapy.

Medications and supplements. The metabolic approach is our primary strategy, developed through the research described above. Current treatments include pharmaceutical medications used off-label and several supplements in high doses, such as vitamin D, curcumin, and resveratrol.

Hyperbaric oxygen. The role of oxygen, particularly hyperbaric oxygen, is underappreciated in cancer treatment. Historically, the work of Judah Folkman, MD, on angiogenesis implied that cancer could be destroyed by drugs which inhibit blood supply to cancer cells. We are now learning that decreasing blood supply actually makes cancers more aggressive.

As cancer cells become more hypoxic, a transcription factor described as hypoxia-inducible factor 1a is released, causing the cancer to become more glycolytic. The data show that the more hypoxic the tumor, the more aggressive.

Conversely, when we feed cancer cells oxygen, that reduces the aggressive nature of the cancer. In my experience, patients with cancer do better with therapies that increase the supply of oxygen to the tissues. Currently, a study is being conducted at Long Island Jewish Medical Center on the use of hyperbaric oxygen in cancer treatment.

Immunotherapy. Our approach to immunotherapy includes hyper­thermia, medications, and botanicals:

Hyperthermia – We employ whole-body hyperthermia. As the cancer cells become more acidic, they also become more susceptible to heat therapy.
Naltrexone – We also utilize low-dose naltrexone, an opioid antagonist, to increase the body's production of endorphins and enkephalins. Met-enkephalin, or opioid growth factor, is particularly effective in inhibiting cancer growth.
Mistletoe – In some cases, treatment includes injections of mistletoe, which we import from Germany. This provides a mild stimulant to the immune system and increases activation of natural killer cells and mature T-cells.
Other botanical supplements – We frequently prescribe supplements such as astragalus to improve immune function.

Ketogenic diet. Frequently patients are told, "It doesn't matter what you eat if you have cancer. Just don't get too thin." In fact, the data shows that cancer thrives on glucose, so carbohydrates are not a good choice of nutrition.

In our practice, patients with glycolytic tumors are prescribed a ketogenic diet (not to be confused with an Atkins diet). To limit carbohydrates and glycolysis, the ketogenic diet consists of 10% to 15% carbohydrates and 5% to 10% protein. The patient consumes protein in such limited amounts that it cannot be converted to carbohydrates. Calories are provided by an intake of 75% to 80% healthy fats, typically medium chain triglycerides such as coconut oil and palm kernel oil. Normal cells are forced to metabolize these fatty acids into ketones. Although the brain and the body can utilize ketones, most cancers have difficulty metabolizing ketones. We combine this dietary approach with other techniques in an inclusive protocol.

No single therapy is currently effective against all forms of cancer. The most promising forms of treatment are metabolic therapies that manipulate the biochemistry of cancer cells to control the disease. In my experience, a comprehensive approach that includes metabolic treatment is usually the most successful.

MARK ROSENBERG, MD
Dr. Rosenberg received his medical degree from Georgetown University School of Medicine and serves as director of the Fellowship in Integrative Cancer Therapy with the American Academy of Anti-aging Medicine, the first and only fellowship of its kind in the United States. His clinical practice in anti-aging medicine is located in Boca Raton at the Institute for Healthy Aging. He is chief medical Officer for LifeLength, which provides lab testing on telomere health as a marker of aging; and chief science director of Research and Development for Vitalmax Vitamins.

Dr. Rosenberg has been involved in the research and development of pharmaceuticals since 1991. In 2001, he developed and patented a drug to aid in the management of obesity and diabetes, and he also has a patent pending for an oral appetite suppressant. He is currently researching novel compounds to treat cancer and has received approval status for a new investigational drug that works in conjunction with chemotherapy.

RESOURCES
CANCER TREATMENT
The Institute for Healthy Aging
The Institute for Healthy Aging
4800 North Federal Highway
Suite B103
Boca Raton, Florida 33431
Phone: 561-939-3898
Fax: 561-886-0981
www.antiagemed.com

CANCER FELLOWSHIP
American Academy of Anti-Aging Medicine
Topics covered in-depth in the 11 fellowship modules include the following: the molecular biology of cancer; genetic and viral predispositions; tumor profiling, individualized chemotherapy, anti­oxidant therapy, leading-edge radia­tion therapy, chemotherapy (old and new drugs), stem-cell transplantation, and off-label pharmaceuticals in cancer treatment; immunosuppression, immuno­deficiency, immunotoxins, and inter­feron therapy; assessment and treatment of therapy-induced conditions; promising emerging treat­ment including avemar therapy, cancer pH manipulation therapy, Coley's toxins, Hoxsey therapy, hyperbaric oxygen therapy, hyperthermia, photodynamic treatment, protocell therapy, and sonodynamic therapy; dietary interventions; and herbal supplementation. Treatment and patient care are presented in the context of the management of an integrative cancer practice.
1801 N. Military Trail, Suite 200
Boca Raton, Florida 33431
Toll-free phone: 888-997-0112
International phone: 561-997-0112
Fax: 561-997-0287
http://www.a4m.com/fellowship-integrative-cancer-therapy.html

EDITORIAL
Nancy Faass, MSW, MPH, is a writer and editor in San Francisco who has worked on more than 40 books for publishers that include Elsevier, Harper, McGraw-Hill, Mosby, New Harbinger, New World Library, North Atlantic, and others. Director of The Writers' Group, she also provides articles, white papers, and writing for the Web. For more information, see www.HealthWritersGroup.com.

Hyperbaric Oxygen Therapy for Cancer Treatment Side Effects
by Nancy Faass, MSW, MPH

Recent studies report increasingly positive outcomes for the use of hyperbaric oxygen therapy with cancer patients. Of the ten latest studies published 2006 to 2012, nine found improved outcomes. In contrast, of ten preceding studies published 2000 to 2006, only four indicated favorable outcomes.

Hemorrhagic cystitis. Research published in 2012, conducted at a university hospital in Shanghai, evaluated outcomes of hyperbaric oxygen therapy for radiation-induced hemorrhagic cystitis. Investigators compared the efficacy of hyperbaric oxygen and hyaluronic acid in a randomized controlled trial involving 36 patients. Researchers found both treatments equally effective at 6-, 12-, and 18-month follow-ups. Decrease in urinary frequency was significant for both treatments at the 6-month follow-up, but at 12 months hyperbaric therapy was no longer effective. However, improvement in pain scores remained significant in both groups at 18 months.¹

Post-surgical brain edema. A large randomized, controlled trial (2011) at a medical school in central China evaluated the effect of hyperbaric oxygen therapy on post-surgical brain edema in 232 patients. Following tumor resection for meningiomas, patients were randomized to a treatment or control group. Although no differences were observed on the third day following surgery, at 15 days after surgery those receiving hyperbaric therapy had "obviously higher" performance and "brain edema in the operative region was definitely smaller." Based on evaluation at the six-month follow-up, researchers reported, "HBO2 therapy is effective in reducing edema formation and neurological deficits after resection."²

Wound healing following throat and neck surgery. A randomized controlled study of 83 patients (2011) at a medical college near Beijing assessed the effect of hyperbaric oxygen therapy on wound healing following pharyngeal and laryngeal cancer surgery. Hyperbaric oxygen was provided to 48 patients using the following protocol: HBO pressure 2 x 10(5) Pa, 110 minutes per day for 5 to 10 days. Patients receiving hyperbaric treatment experienced significantly better healing:

• Myocutaneous or forearm flaps – 27.5 days to heal compared with 45 days in control group
• Pharyngeal fistulas – 8.5 days compared with 14 days in controls
• Infected wounds – 5.9 days compared with 8.6 days in controls

The study concluded that "hyperbaric therapy is an effective and powerful treatment for late healed post-operative wounds in carcinoma surgery."³

Radiotherapy side effects with oropharyngeal and nasopharyngeal cancer. A randomized trial (2009) conducted at an urban cancer center in the Netherlands evaluated quality of life and side effects for early hyperbaric oxygen therapy following radiotherapy. Nineteen patients were randomly assigned to a protocol of HBOT: 30 sessions at 2.5 ATA (15 msw) with oxygen for 90 minutes daily, 5 days per week. Follow-up questionnaires were obtained at 2, 4, and 6 weeks and 3, 6, 12, and 18 months. Researchers concluded, "Patients randomized for hyperbaric oxygen after radiotherapy had better quality of life scores for swallowing … xerostomia, and pain in mouth."⁴

Liver resection. A Japanese study published in 2011 evaluated the effects of hyperbaric oxygen therapy on 41 patients following liver resection, provided to minimize the requirement for perioperative blood transfusions. Patients with similar preoperative assessments were randomly assigned to hyperbaric therapy. The treatment protocol consisted of HBOT at 2.0 atm. with inhalation of 100% oxygen for a duration of 60 minutes, performed at 3, 24, and/or 48 hours after the hepatectomy. In contrast with the control group, there were no fatal complications in the hyperbaric group, and patients had better blood chemistry markers and lower incidence of hyperbilirubinemia.⁵

Lymphedema after breast cancer surgery. A randomized study conducted in London (2010) evaluated the effects of hyperbaric oxygen therapy on 58 women post-surgery for early breast cancer. Protocol utilized was 100% oxygen at 2.4 atmospheres absolute for 100 minutes on 30 occasions over 6 weeks. In the final evaluation of 46 patients, no significant differences were observed between hyperbaric-treated patients and controls in terms of limb volume. Researchers concluded, "No evidence has been found of a beneficial effect of HBO on treatment of arm."⁶

Radiation proctitis. A randomized, controlled, double-blind crossover trial (2008) evaluated the long-term risk of radiation-induced injury in conditions such as refractory radiation proctitis. Based on a design by a research center in Columbia, SC, patients were randomized to hyperbaric oxygen at 2.0 atmospheres absolute or sham treatment at 1.1 atmospheres with subsequent crossover. Outcomes were evaluated at 3 and 6 months and at years 1 through 5. "Hyperbaric oxygen therapy significantly improved the healing responses in patients with refractory radiation proctitis, generating an absolute risk reduction of 32%. ... Other medical management requirements were discontinued and advanced interventions were largely avoided. Enhanced bowel-specific quality of life resulted."⁷

A second study of radiation proctitis, using an open, randomized, parallel, prospective design (2007), was conducted at Navy SEAL Hospital in Jakarta, Indonesia. Of the 65 patients studied, 32 patients received HBOT. Researchers concluded, "The study showed that HBOT decreased acute and late side effects, and also improved the quality of life of patients with radiation proctitis.⁸

Side Effects & Quality of Life Scores
Post-Pelvic Radiation
                                                         HBOT        Control
Acute side effects                                  0.7           44.1
Late side effects                                –19.6          33.6
Quality of life post treatment               19.7            4.5
Quality of life 6-month follow-up          15.2            2.5

A third study of radiation-induced hemorrhagic proctitis (2006) was conducted at the University of Cincinnati to evaluate nine patients. The median age was 75 (range 66 to 83); unresolved issues included chronic bleeding, and anemia. Symptoms had not resolved, despite hospitalization, transfusions, electrocautery, or coagulation therapy. At an average of 17 months after HBOT treatment, seven patients had complete resolution of rectal bleeding, and the other two exhibited partial resolution.⁹

Recurrent high-grade gliomas. The division of hyperbaric medicine at a university hospital in southern Japan conducted a study (2007) evaluating 25 consecutive patients who had previously received radiation with chemotherapy for gliomas. In this study, patients were treated with radiotherapy immediately following HBOT (2.5 atmospheres absolute for 60 minutes). Among 14 patients with anaplastic astrocytomas, median survival time was 19 months; among the 11 with glioblastoma multiforme, median survival was 11 months.¹⁰ [For comparative survival rates, see the article by Gorter and Peper in this issue under Outcomes: Brain Cancer.]

An open question for clinicians. What accounts for these improved outcomes? Are treatment protocols better calibrated? Is the new technology more effective? In a field in which every gain is hard won, these outcomes suggest the value of further scrutiny.

Notes
1. Shao Y, Lu GL, Shen ZJ. Comparison of intravesical hyaluronic acid instillation and hyperbaric oxygen in the treatment of radiation-induced hemorrhagic cystitis. BJU Int. 2012 Mar;109(5):691-4. Epub 2011 Sep 2.
2. Tang X, Yin X, Zhang T, Peng H. The effect of hyperbaric oxygen on clinical outcome of patients after resection of meningiomas with conspicuous peritumoral brain edema. Undersea Hyperb Med. 2011 Mar-Apr;38(2):109-15.
3. Jiang W, Liang D, Zhang H, Shang W, Wang P, Li W. [The effect of hyperbaric oxygen therapy on treatment of late healed wounds after pharyngeal and laryngeal surgery] [Article in Chinese]. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2011 Jan;25(1):14-5, 19.
4. Teguh DN, Levendag PC, Noever I, et al. Early hyperbaric oxygen therapy for reducing radiotherapy side effects: early results of a randomized trial in oropharyngeal and nasopharyngeal cancer. Int J Radiat Oncol Biol Phys. 2009 Nov 1;75(3):711-6. Epub 2009 Apr 20.
5. Ueno S, Sakoda M, Kurahara H, et al. Safety and efficacy of early postoperative hyperbaric oxygen therapy with restriction of transfusions in patients with HCC who have undergone partial hepatectomy. Langenbecks Arch Surg. 2011 Jan;396(1):99-106. Epub 2010 Nov 11.
6. Gothard L, Haviland J, Bryson P, et al. Randomised phase II trial of hyperbaric oxygen therapy in patients with chronic arm lymphoedema after radiotherapy for cancer. Radiother Oncol. 2010 Oct;97(1):101-7. Epub 2010 May 31.
7. Clarke RE, Tenorio LM, Hussey JR, et al. Hyperbaric oxygen treatment of chronic refractory radiation proctitis: a randomized and controlled double-blind crossover trial with long-term follow-up. Int J Radiat Oncol Biol Phys. 2008 Sep 1;72(1):134-43. Epub 2008 Mar 14.
8. Sidik S, Hardjodisastro D, Setiabudy R, Gondowiardjo S. Does hyperbaric oxygen administration decrease side effect and improve quality of life after pelvic radiation? Acta Med Indones. 2007 Oct-Dec;39(4):169-73.
9. Girnius S, Cersonsky N, Gesell L, Cio S, Barrett W. Treatment of refractory radiation-induced hemorrhagic proctitis with hyperbaric oxygen therapy. Am J Clin Oncol. 2006 Dec;29(6):588-92.
10. Kohshi K, Yamamoto H, Nakahara A, Katoh T, Takagi M. Fractionated stereotactic radiotherapy using gamma unit after hyperbaric oxygenation on recurrent high-grade gliomas. J Neurooncol. 2007 May;82(3):297-303. Epub 2006 Nov 22.