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Fever therapy in oncology.

One of the basic tenets of naturopathic medicine is to work with the vis medicatrix naturae. To remove our patients' obstacles to health, allowing their bodies to heal using this innate healing response. With advancements in our understanding of the human body and the biological sciences as a whole, one of the new incarnations of this has been termed evolutionary medicine or Darwinian medicatrix naturae. This newly emerging field looks at normal bodily processes such as inflammation, fever, and moods, and describes why such traits have been selected through evolution. I had the good pleasure of taking a course taught by Larry Dill, PhD, while at Simon Fraser University's Biological Sciences department, called "Darwinian Medicine." Our textbook was called Why We Get Sick, by Nesse and Williams. (1) Both Dr. Dill's class and this book certainly contributed to my becoming a naturopathic physician, and ultimately focused on oncology.

This article will focus on the ancient immunologic response known as the fever. Fever causes many unpleasant symptoms, but has been shaped by natural selection over millions of years to fight infection and other processes. Physiologist Matt Kluger says, "There is overwhelming evidence in favor of fever being an adaptive host response to infection that has persisted throughout the animal kingdom for hundreds of millions of years." (2) In his laboratory at the Lovelace Institute, he has shown that even lizards will find warmth to raise their temperature 2 [degrees]C when infected. If they are not able to find warmth, they are likely to die. When rats are put into cooler rooms, they activate heat conservation mechanisms that cause a 2[degrees] fever. The average human core body temperature is 36.5[degrees], the actual physiological and immunological benefit of a fever begins at 38.5[degrees], again an increase of 2[degrees]. Fever results from the activation of a very sophisticated evolved mechanism. Julius Wagner Jauregg won the 1927 Nobel Prize in physiology or medicine for his treatment of syphilis. He noted that many of his patients with syphilis improved after getting malaria, so he purposely infected thousands of syphilis patients with malaria. He achieved remission rates of 30% as a result of the fevers caused by the malaria.

All doctors are taught that fever remains one of the most important hallmarks of disease, but nonetheless, it is given very little attention in medicine today. Since antipyretic drugs such as ASA, ibuprofen, and other nonsteroidal anti-inflammatory drugs have become available, fever has become something to be suppressed; apparently the war against fever has been won. However, as already discussed, fever is the body's response to pathogens and other disease processes. Despite the discomfort that fever can cause, it is a process that should be allowed its due time and attention. Should fever rise too high, symptoms such as delirium, seizures, and lasting tissue damage are possible. So of course there are cases in which suppression of a profound fever is needed; fever like everything else is not infallible. However, the German Interdisciplinary Working Group on Hyperthermia has been conducting studies on the use of > 41.5 [degrees]C fever therapy, called extreme whole body hyperthermia, and has shown this treatment to be safe and well tolerated, absent the feared symptoms of high fever. (3) This topic certainly requires some serious attention and research.

Now as far as cancer is concerned, the fact that there have been repeated examples of spontaneous regressions and/or remissions of metastatic disease following febrile illnesses has formed the basis for fever therapy in oncology. Such profound responses have been documented repeatedly in the medical literature over the past century. (4-87)

Another basis for fever therapy is the weight of evidence showing an inverse relationship between the number of febrile illnesses in a person's life and subsequent risk for cancer. As far back as 1854, Lawrence published his observations that patients with cancer had "a remarkable disease-free history." (88) Schmidt termed this a febrile diathesis, and he too correlated a lack of fevers to cancer risk in his study of 241 cancer patients. (89) Angle compared 300 patients with cancer against 300 patients without, and he also found an increased cancer risk with fewer infectious diseases. (90), (91) Newhouse found fewer incidences of mumps, measles, and rubella in a study of 300 women with ovarian cancer when compared with an age-matched control group. (92) Ronne linked missing childhood measles with an increased risk for various cancers. In his cohort of 353 without childhood measles, 21 developed cancer versus only 1 in his case-control of 230 patients with a positive history of measles (hazard ratio < 0.001). (93) Such data beg for further research on this potentially important subject matter.

If it is true that fever is a friend and not foe, and that experiencing fevers through life decreases risk for cancer, what about fever in those already diagnosed with cancer? Dr. William Coley perhaps best documented spontaneous remissions of cancer following infections with fever. Of course, the use of bacterial and viral products such as the famous Coley's toxins has long been studied in oncology. (94-110) The remainder of this discussion will instead focus on exogenously induced hyperthermia, more specifically, 38.5 to 400 fever-range whole body hyperthermia (FR-WBHT). In the early 1980s, clinical research on passive infrared heating devices began by those such as Heckle and von Ardenne (111), (112) The majority of the research on FR-WBHT to date is on its combined use with chemotherapy, called thermochemotherapy. In this setting, the FR-WBHT is being used, amongst other reasons, to provide better perfusion of the chemotherapy due to the increased blood circulation during a fever. With considerable animal data and limited human data indicating benefit over chemotherapy alone, confirmation by larger randomized trials is far overdue. (113-125)

As I have provided close to 200 FR-WBHT treatments to date, and I myself have experienced our FR-WBHT treatment firsthand, I will now provide a review of the treatment from both a doctor's and patient's perspective. First, absolute contraindications such as preexisting arrhythmia (ECG), thrombocytopenia, severe microcytic anemia (hematology), bleeding disorders, and active bleeds must be screened for. Issues such as active brain lesions, severe effusions, edema, or liver and kidney disease are relative contraindications that must also be considered. After screening, the treatment requires at least 6 hours of fasting, emptying the bladder, and a sodium phosphate enema. When patients arrive for treatment, they change into comfortable and light clothing, and put on cotton gloves and socks to ensure complete skin coverage. Conscious sedation is offered, and is an option that some patients choose for the treatment. Of note, all patients who have had the treatment, both under conscious sedation and without, have decided to have future treatments without sedation, due mainly to the ease of recovery. An external or internal catheter is then placed as intravenous saline and dextrose and administered concurrently through the whole treatment, to prevent dehydration and hypoglycemia respectively. When the patient enters the treatment room, the doctor places the monitoring unit which continually measures rectal core body temperature, pulse oximetry, heart rate, ECG, respirations, and blood pressure throughout the treatment. Once the monitoring system is in place and ready, the doctor secures the skirting or tent that envelops the treatment table and patient (all but the head), and then the 6 infrared heating lamps are turned on. It takes 2 to 3 hours to raise the core temperature to the desired range of 38.5[degrees] to 40[degrees] during the heating phase, we maintain that temperature for 1 to 2 hours during the retention phase, and then finally the patient takes approximately another 1 to 2 hours in the cooling phase. A typical treatment lasts 5 to 6 hours. If patients choose conscious sedation, they will feel quite sedated at the end of the treatment and for the rest of that evening, back to normal the following day. For me, and the rest of the patients who choose no sedation, I felt refreshed and rejuvenated about an hour after the treatment, and rehydrated and ate a full meal. I did note mild edema in my hands and feet, which resolved by the next morning. We encourage our patients to hydrate themselves with electrolytes and fluids for the 24 to 48 hours after the treatment. To date, we have had 2 patients with catheterization issues, and 2 patients with minor blistering of their skin which became exposed during treatment (due to being sedated), with no other adverse events. We are collecting data on all our patients with hopes of publishing once we have adequate numbers. I am also currently working on a best case series in conjunction with Reliable Cancer Therapies from Belgium.

So what exactly is happening to the body's physiology during a fever? Fever is a complex neuroendocrine response able to reset the temperature regulator found in the hypothalamic area. (126) It has been determined that pyrogens are the primary substances that induce fevers. (127) Pyrogen synthesis and release are predominantly due to the cytokine messengers IL-1 and prostaglandin E2 (PGE2). More recently it has been discovered that the toll signaling pathway provides the molecular link, the stimulation, for the many pyrogens that these cytokines induce. (128), (129) IL-1 has been termed the endogenous pyrogen and lymphocyte activating factor. (127), (130) It is a very important intracellular messenger between cells of the immune system such as macrophages and B and T lymphocytes, and is also a stimulator of cyclooxygenase-2 (COX-2) biosynthesis. II-1 increases 22- to 100-fold 30 to 90 minutes after toll-like receptor (TLR) activation, making this the most relevant pyrogen for understanding fever. Just looking at some of the downstream effects of macrophages alone, they then produce a series of pro-inflammatory cytokines such as IL-1, 2, and 6; tumor necrosis factor alpha; interferon-a; and interferon-y. (131) The role of PGE2 in mediating fever is now also well documented. (132) PGE2 acts on the thermal regulatory area of the hypothalamus and resets it to a higher level of temperature, producing the febrile response. COX-1 and -2 are the rate-limiting enzymes in PGE2 synthesis, which explains why antipyretic therapy is aimed at inhibiting COX-1 and -2. Natural killer cell cytotoxicity increases with increasing temperatures, due mainly to IL-2 and interferon alpha. (133) Lastly, heat shock proteins (HSPs) are highly conserved constituents of cells classified into several families. (134), (135) Although a thorough discussion of HSPs and their varied effects in oncology is not possible in this article, suffice it to say that these proteins induced by FR-WBHT are the focus of some research today. Fever is able to benefit so many of the molecular targets of medical oncology.

At a time when we continue to look for ways of improving outcomes in the metastatic patient, FR-WBHT requires much more attention. This is a treatment that makes use of an ancient defense mechanism evolved and designed to fight infection and other invaders. Fever is a process that has repeatedly been documented to cause regressions and remissions of metastatic disease. Fever therapy is a treatment that has long been shown to be of benefit alongside chemotherapy, as well as when used on its own. Of course, FR-WBHT has not yet been confirmed by larger and better designed trials, but the existing data also show that it improves quality of life. Most patients report a feeling of rejuvenation and increased well-being following this treatment. Fever has far-reaching and varied effects on several important cytokines such as IL-1, IL-2, COX-1 and -2, and PGE2 and immunological cells such as macrophages, and even induces HSPs. Having now used FR-WBHT in over 100 patients with metastatic disease, I am able to report that, when administered appropriately, FR-WBHT is a safe and promising cancer therapy. I look forward to publishing our findings through a best case series as well as in retrospective and prospective trials. I believe that it will be in arenas such as fever that biologists, oncologists, researchers, and naturopathic physicians will meet--each of us trying to best understand how to make the best use of this highly evolved and ancient response.

Special Thanks

I would like to acknowledge and thank my friend and colleague Gian Franco Baronzio, MD, for allowing me to use references from his textbook Hyperthermia in Cancer Treatment: A Primer. (136)

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Notes

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by Gurdev Parmar, ND, FABNO

Dr. Parmar is a respected leader in the field of integrative oncology. He and his wife, Dr. Karen Parmar, launched the Integrated Health Clinic in 2000 and have since facilitated its growth to become one of the largest and most successful integrated health-care facilities in Canada. Dr. Parmar was the first Canadian naturopathic physician to hold a fellowship to the American Board of Naturopathic Oncology (FABNO), a board certification as a cancer specialist. Dr. Parmar has been a consulting physician at the Lions Gate Hospital chemotherapy clinic since 2008, creating the first integrative oncology service in any chemotherapy hospital in the country. He has established an exceptional collaborative relationship with medical oncologists, radiation oncologists, surgical oncologists, and other practitioners to ensure that patients are provided the most current evidence-based complimentary treatments possible. Over the past few years, Dr. Parmar has worked hard at bringing hyperthermia to Canada, and his clinic has become the first in North America to offer locoregional hyperthermia for cancer patients. He is on the editorial board of the international Oncothermia Journal. Dr. Parmar serves on the board of the Oncology Association of Naturopathic Physicians, and chairs its education committee. He is an active licensed member of the College of Naturopathic Physicians of British Columbia, the state of Arizona, and the American Society of Clinical Oncology.
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