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Immunotherapy Series – What is REAL Hyperthermia?

Would the REAL hyperthermia please stand up!

Good science needs no marketing.

The two previous posts in this series on hyperthermia dealt with the background and history of hyperthermia. It is time for some details—time for some receipts.

What is hyperthermia from a cancer treatment perspective? Not marketing, just good science.

First, I need to review what hyperthermia is. To know what` hyperthermia is will help to know what hyperthermia is not from a cancer treatment perspective.

Definition

To better understand hyperthermia, we must define hyperthermia. According to a 2013 article, Temperature Matters! And Why It Should Matter to Tumor Immunologists, hyperthermia is a “…forced heating of the body or tissues in the absence of a change in the hypothalamic temperature set point…” [1]. A 2020 article in the journal, Frontiers of Immunology, defined it better, “Hyperthermia is a method of killing cancer cells or impeding their growth by increasing tissue temperature with an external heat source for a certain period of time” [2]. Simply stated, hyperthermia is the mechanical mimicking of a fever that is similar in the characteristic of fever in temperature but not identical to a fever in all effects, for a duration of time. It is about dose and duration.

Dose and duration

According to the article, Hyperthermia can alter tumor physiology and improve chemo- and radio-therapy efficacy published in 2020, “the impact of hyperthermia depends on exposure time and temperature” [3]. Hyperthermia is about dose and duration. I like to call it the rule of hyperthermia dose and duration. Dose is the temperature range, which I will discuss in more detail below. Duration is the time spent at the optimal dose. To achieve the optimal treatment effects of hyperthermia, one must achieve both dose and duration. Dose can not be sacrificed for duration, nor can duration be sacrificed for dose. They are not mutually exclusive. In fact, they work together in total harmony. For optimal hyperthermia effect, they must occur together. This is dose and duration is no different than the dose-response curves of conventional pharmaceutical medications. Optimal dose for optimal duration equals optimal results. Anything less is sub-optimal. Just an aside and often overlooked, this same dose and duration point is important in the use of intravenous vitamin C and other holistic cancer treatments.

To embrace Holistic, Integrative cancer treatment is to embrace science. Contrary to some thought, Holistic and Integrative cancer therapies are heavy in science. One doesn’t throw away science to practice Holistic, Integrative medicine. Actually, it is the science that pushes Dr. Lodi and myself to a more Holistic, Integrative approach to cancer therapies.

Look at the fever response. Fever has a dose component (temperature) and a duration component (time). A fever rarely lasts just 30 minutes. If left to run its course, a fever during an infection will often last hours, peak and sustain a temperature, and then return to normal. Even with a fever, it is about dose and duration. The two are required for optimal immune effects to clear the body of the invader. Likewise, hyperthermia is about dose and duration. Hyperthermia mimics the fever response; thus, 30 minutes need not apply here as well. Similarly, a dose (temperature) that is too low also misses the mark—more on temperature below.

Duration

Here the temperature duration, effect, and target are dictated by the organization or country involved. Germany has led the way in the research, application, and experience of hyperthermia. I like to use the Ganzkörper-hyperthermie (GKHT) guidelines published in 2018 by the German Society for Hyperthermia Scientific Advisory Board definitions of mild, moderate, and extreme GKHT, because it combines both the dose and duration [4].

Mild

Mild GKHT Mild GKHT
Duration < 30 minutes > 30 minutes
Indication Wellness Rehabiliation, orthopedics, rheumatology

Moderate

Moderate GKHT Moderate GKHT
Duration < 180 minutes > 180 minutes
Indication Rheumatology, Dermatology, Psychology, Immunology, Oncology, Environmental medicine Oncology, chronic infections

Extreme (severe)

Extreme GKHT
Duration 60-120 minutes
Indication Oncology, chronic infection

Dose (Temperature)

Here, the same German Society for Hyperthermia Scientific Advisory Board above dictates the temperature effect and target. Add dose to the duration, and the real hyperthermia stands up and more—stands out.

Mild

Mild GKHT Mild GKHT
Duration < 30 minutes > 30 minutes
Indication Wellness Rehabiliation, orthopedics, rheumatology
Temperature < 38.5 °C (101.3 °F) < 38.5 °C (101.3 °F)

As you can see, mild is, well, mild. It is short in duration and low in temperature and has limited to no therapeutic benefit in cancer treatment. Here too, hyperthermia’s full therapeutic potential is seen through the lens of the combined dose and duration.

Other sources may reference mild hyperthermia in the range of 39-41 °C [5]. But, the temperature range is just a reference to dose and ignores duration, as highlighted above. Hyperthermia cannot be clearly defined without both dose and duration. Temperatures greater than 39 °C increase immune infiltration of the tumor microenvironment [6], cause vasodilation, and increase tumor microenvironment oxygenation [7] [8], which is counter to the hypoxic environment in the tumor and local tumor microenvironment. Know this, mild hyperthermia, 39 °C, does not provide direct cancer-killing action—cytotoxicity.

Moderate

Moderate GKHT Moderate GKHT
Duration < 180 minutes > 180 minutes
Indication Rheumatology, Dermatology, Psychology, Immunology, Oncology, Environmental medicine Oncology, chronic infections
Temperature 38.5 – 40.5 °C (101.3 – 104.9 °F) 38.5 – 40.5 °C (101.3 – 104.9 °F)

The full therapeutic potential of hyperthermia is again seen with the combination of dose and duration. As with mild hyperthermia, different sources will also reference different temperatures alone, 41-42 °C, as moderate hyperthermia 2. In hyperthermia, the combined importance of dose and duration appears to be ignored in much of the general scientific literature..

Extreme (severe)

Extreme GKHT
Duration 60-120 minutes
Indication Oncology, chronic infection
Temperature > 40.5 °C (104.9 °F)

In contrast to the immune infiltrating effects from 39 -40.5 °C, temperatures above 40.5 °C induce immunogenic cell death 4. Beyond duration, the effects vary with the dose of temperature.

When it comes to the treatment of cancer, moderate or extreme hyperthermia need only apply. Only at the doses and duration seen with moderate and extreme hyperthermia are the full anti-cancer effects of hyperthermia brought to bear against the tumor and the local tumor microenvironment. Anything less in dose and duration (see above) limits the anti-cancer effects and, worse, may even be harmful. Did I catch your attention? Research points to inadequate, unsuccessful hyperthermia as the potential stimulus for angiogenesis, aggressive proliferation, and epithelial to the mesenchymal transition of cancer [9] [10] [11] [12] [13], which are essential to cancer growth and the metastatic spread of cancer. These facts are why the general, clinically accepted temperature range for cancer’s therapeutic treatment is 40-45 °C [14]. To be redundant, it is about dose and duration.

It would be oversimplified to say that these are the only classifications and accepted temperature ranges of hyperthermia, but they are not. Other sources reference fever-range hyperthermia, 39-40 °C, mild temperature hyperthermia as 41-43 °C, and > 43 °C as ablative hyperthermia [15]. If you look enough, there are even more temperature ranges and definitions. There is no uniform, international standardization here, and that is not necessarily a bad thing. I am afraid that all this conventional medical standardization has given us nothing but group think with the loss of the ability to think critically.

Measurement

Also fundamental and often missed is the measurement of the temperature. The temperature measured must be core temperature. The forced heating of the body induces a corresponding cooling reaction. We call this sweating. Those in the more humid areas of the world know this physiologic response all too well.

What is the best way to measure temperature? Surface temperature is the most common and easiest way to measure temperature. But does surface temperature correlate with core temperature? Surface temperature monitoring in hyperthermia does not adequately reflect core temperature. It becomes objectively impossible due to the intense sweating induced by the body in response to the mechanical heat of hyperthermia. There are advocates for using skin surface temperature for the correlation of internal core temperature; however, this method is not reliable because of the cooling and sweating of the body in response to hyperthermia.

Monitoring

Hyperthermia is not a simple procedure. In addition to the continuous core temperature monitoring, hyperthermia requires constant monitoring of the cardiovascular and pulmonary systems. Proper dose and duration can strain both systems—especially the cardiovascular system. Any proposed hyperthermia that does not provide constant monitoring (core temperature, cardiovascular, or pulmonary) is either not real hyperthermia or not good hyperthermia.

Frequency

It is not enough to focus on dose and duration; one must keep in mind frequency. Inadequate and excessive treatment frequency can induce thermotolerance [16] and result in less than optimal results. Hyperthermia-induced thermotolerance is the sub-lethal hyperthermic induction of short-term, adaptive resistance to thermal stress that renders the surviving heated cells resistant to additional heat stress, which often requires higher dosing. In the holistic, integrative cancer movement, we must recognize that we can fall into the same trap of the flawed conventional mindset of the same dose, same duration, and same frequency of the one-size-fits-all protocol medicine.

Now, what hyperthermia is not.

Defining what hyperthermia is, makes it really simple to identify what hyperthermia is not. Just look above and add not. But, to stick to the details, research, and the rule of dose and duration, hyperthermia is not:

  • a steam box
  • a steam tent
  • a sauna
  • a hot bath
  • a 30-minute procedure
  • a sub-optimal temperature
  • a simple process of sweating
  • measured by surface temperature
  • a patient-directed procedure
  • a monitoring free procedure
  • Anything with the head involved in the heating process

Yes, I have heard all of the above described as hyperthermia, and I have seen many of the items in this list advertised as hyperthermia, but hyperthermia they are not.

Make no doubt, these techniques may raise the temperature just a little bit, and they also will induce sweating, no doubt. But, they don’t follow the rule of dose and duration of hyperthermia. They don’t follow the evidence. They woefully miss the mark and thus miss the full potential therapeutic benefits of hyperthermia, and worse, they may even be harmful. Non-hyperthermic heating may still have some detoxification benefits, but it should not be used for hyperthermia in cancer treatment. As a result, they are marketing, not good science.

Hyperthermia dose and duration are very similar to the experience of Dr. William Coley. The absence of a fever, or a limited fever, missed the mark and provided little to no benefit in tumor reduction. However, the right fever, defined by Dr. Coley as 40 – 42 °C, with a more extended fever response, governed by his experience, yielded not only tumor reduction and elimination (spontaneous regression) but also produced decades and decades of no cancer. That is not curing. That is healing. Remember, the Hebrew word for physician, Rāphè, can be translated as healer.

I started this post off by saying, good science needs no marketing. Let me finish that thought with this, marketing-driven medicine is science fiction, not good science.

_______

[1] Repasky EA, Evans SS, Dewhirst MW. Temperature Matters! And Why It Should Matter to Tumor Immunologists. Cancer Immunol Res. Oct 2013;1(4):210-216; DOI: 10.1158/2326-6066.CIR-13-0118

[2] Li Z, Deng J, Sun J, Ma Y. Hyperthermia Targeting the Tumor Microenvironment Facilitates Immune Checkpoint Inhibitors. Front Immunol. Nov 2020. https://doi.org/10.3389/fimmu.2020.595207,

[3] Dunne M, Regenold M, Allen C. Hyperthermia can alter tumor physiology and improve chemo- and radio-therapy efficacy. Advanced Drug Delivery Reviews. 2020;163-164:98-124. https://doi.org/10.1016/j.addr.2020.07.007

[4] Wehner M, Wey S, Meyer A. 2018. Full Body Hyperthermia. Retrieved from https://www.heckel-hyperthermia.com/images/downloads/Leitlinie_GKHT_OKT2018.pdf.

[5] Skitzki JJ, Repasky EA, Evans SS. Hyperthermia as an immunotherapy strategy for cancer. Curr Opin Investig Drugs. 2009;10(6):550-558.

[6] Datta NR, Kok HP, Crezee H, Gaipl US, Bodis S. Integrating Loco-Regional Hyperthermia Into the Current Oncology Practice: SWOT and TOWS Analyses. Front Oncol. 2020;10:819. Published 2020 Jun 12. doi:10.3389/fonc.2020.00819

[7] Song CW, Park HJ, Lee CK, Griffin R. Implications of increased tumor blood flow and oxygenation caused by mild temperature hyperthermia in tumor treatment. Int J Hyperthermia. (2005) 21:761–7. 10.1080/02656730500204487

[8] Song CW, Shakil A, Osborn JL, Iwata K. Tumour oxygenation is increased by hyperthermia at mild temperatures. 1996. Int J Hyperthermia. (2009) 25:91–5. 10.1080/02656730902744171

[9] Kong J, Pan B, Ke S, Dong S, Li X, Zhou A, Zheng L, Sun WB. Insufficient Radiofrequency Ablation Promotes Angiogenesis of Residual Hepatocellular Carcinoma via HIF-1α/VEGFA. PLoS One. 2012;7:e37266.

[10] Zhang N, Wang L, Chai ZT, Zhu ZM, Zhu XD, Ma DN, Zhang QB, Zhao YM, Wang M, Ao JY, Ren ZG, Gao DM, Sun HC, Tang ZY. Incomplete Radiofrequency Ablation Enhances Invasiveness and Metastasis of Residual Cancer of Hepatocellular Carcinoma Cell HCCLM3 via Activating β-Catenin Signaling.PLoS One. 2014;9:e115949.

[11] Ke S, Ding XM, Kong J, Gao J, Wang SH, Cheng Y, Sun WB. Low temperature of radiofrequency ablation at the target sites can facilitate rapid progression of residual hepatic VX2 carcinoma. J Transl Med. 2010; 8:73.

[12] Wan J, Wu W, Chen Y, Kang N, Zhang R. Insufficient radiofrequency ablation promotes the growth of non-small cell lung cancer cells through PI3K/Akt/HIF-1α signals, Acta Biochimica et Biophysica Sinica. Apr 2016;48(4):371–377. https://doi.org/10.1093/abbs/gmw005

[13] Bu J, Lee TH, Kim IS, Cho Y-H. Microfluidic-based mechanical phenotyping of cells for the validation of epithelial-to-mesenchymal-like transition caused by insufficient heat treatment. Sens Actuators B: Chemical. 2017;244:591—598. https://doi.org/10.1016/j.snb.2017.01.049

[14] Mallory M, Gogineni E, Jones GC, Greer L, Simone CB. Therapeutic Hyperthermia; The old, the new, and the upcoming. Critical Reviews in Oncology/Hematology. Jan 2016;97:56-64. https://doi.org/10.1016/j.critrevonc.2015.08.003

[15] Li Z, Deng J, Sun J, Ma Y. Hyperthermia Targeting the Tumor Microenvironment Facilitates Immune Checkpoint Inhibitors. Front Immunol. Nov 2020. https://doi.org/10.3389/fimmu.2020.595207,

[16] Overgaard J. The current and potential role of hyperthermia in radiotherapy. Int J Radiat Oncol Biol Phys. (1989) 16:535–49. 10.1016/0360-3016(89)90470-7


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