Hyperthermia

Hyperthermia is an emerging and promising cancer therapy that refers to the use of heat and the therapeutic effects of raising body temperature to treat malignant tumors [1]. It can be applied alone (more rare) or in conjunction with other conventional treatments (more common) such as chemotherapy, radiation and immunotherapy [1] [2]. When combined with standard of care treatments clinical data is encouraging [2] [3]. Improved outcomes and increased survival times have been demonstrated in some cases, but proven clinical efficacy for a wide range of cancers is an ongoing area of research [1].

There are three main categories of hyperthermic treatment, which are based on how the treatment is administered. These are local, regional, and whole-body hyperthermia. Local hyperthermia is defined as increasing the temperature of local tumors. It is often applied for superficial tumors near or on the surface of the skin [1]. Regional hyperthermia involves perfusing (passing fluid through) organs or limbs with heated liquid. It is applied for deep-seated tumors and often combined with chemotherapy or radiation [1]. Whole-body hyperthermia is generally applied for cases of metastatic (widespread) cancer [1]. There are various different methods of applying heat, which include microwave, infrared, magnetic, and photothermic therapy amongst others [1].

There is a significant body of clinical research on hyperthermia [1]. Clinical trials in patients with various cancers at different disease stages have shown that hyperthermia can help to prolong life and reduce recurrence when used in combination with radiotherapy and chemotherapy [4]. Data supports the use of hyperthermia in the treatment of multiple cancer types including cervix, breast, head and neck, melanoma, sarcoma, liver, glioblastoma and pancreatic cancer [4].

Despite its scientifically validated clinical benefits and therapeutic applications, some clinical and technical issues still persist with conventional hyperthermia such as an inability to discriminate between target malignant tumors and healthy tissues, which can cause side effects [5]. Nanotechnology is expected to have great potential and may play a significant role in revolutionizing current methods of hyperthermia treatment [5].

History of Hyperthermia

The concept of using heat for the treatment of cancer is not a novel approach, but rather one of the oldest recorded methods known to man. Records of the use of hyperthermia date back to around 3000 BC, which describe the use of heat to burn tumor masses (otherwise known as cauterization) in ancient Egypt, India, and China [6]. The use of natural heat sources such as hot mud baths and volcanic steam have also been widely applied for general health purposes [6].

The term hyperthermia is made up of two Greek words: hyper (rise) and therme (heat) [7].** It refers to the increasing of body temperature or select tissues to achieve a specific therapeutic effect [7]. **The use of high temperature was a common method in various ancient cultures to treat a range of different diseases, including cancer [7]. Heat was considered to have sacred properties in ancient times and associated with the healing power of the sun. It was used to treat locally affected body parts and also for generalized health benefits [7].

In ancient Greece and Rome many physicians believed that the knowledge of how to control human body temperature would allow them to cure all diseases, even cancer [7]. Parmenides, an ancient Greek philosopher, was convinced of the healing power of hyperthermia and stated: “Give me the power to produce fever and I will cure all diseases” [7]. Hippocrates, the so-called “Father of Medicine” shared this viewpoint and asserted that if a disease was not curable by heat it must be incurable, as illustrated by his words: "What medicines do not heal, the lance will; what the lance does not heal, fire will.” [7]

The first scientific paper on hyperthermia was published by a German surgeon Carl D. W. Busch in 1866 in which he described the case of a woman with an advanced facial sarcoma [7]. After the surgical removal of the tumor the patient fell ill with a bacterial skin infection (erysipelas), which caused a high fever, and subsequently led to tumor regression [7]. This was the first reported case indicating that high temperatures could selectively kill cancer cells without affecting healthy cells [7].

In 1891, American Surgeon William B. Coley developed a toxin that caused the erysipelas infection and its typical fever. It was termed Coley’s toxin and applied to treat various types of cancer for over a century [7]. Coley compiled data that showed his treatment increased the five year survival rate from 28% to 64% in patients with inoperable tumors [7]. He also noted that the higher the temperature of the fever provoked in a patient the greater the impact on survival times [7]. It is for this reason that Coley is widely considered the father of the modern use of hyperthermia and immunotherapy for cancer [7]. Coley’s findings marked the beginning of modern hyperthermia therapy and are considered to be pioneering work in the field of immunotherapy [6]. However, largely due to technical difficulties, it was not until the 1970s and 1980s that hyperthermia began to be more widely researched and considered by the medical community as a serious alternative or adjunct to gold-standard cancer therapies (surgery, chemotherapy and radiation) [6].

Research on Hyperthermia

There is currently a large body of clinical research on hyperthermia as a cancer treatment and it is becoming ever more widely accepted as an adjunct therapy to increase the efficacy of standard of care treatments [4]. Many clinical studies have demonstrated that the addition of hyperthermia to radiotherapy or chemotherapy significantly improves tumor control and patient survival rates [5].

A 2022 review of 115 scientific papers on hyperthermia reveals that the temperature range of 41–44 °C induces toxicity in cancer cells while leaving healthy cells unharmed [8]. The review states that clinical trials conducted on the effects of hyperthermia report significant reductions in tumor size when used in conjunction with other therapies. However, when applied alone the anticancer effects of hyperthermia may not be enough to significantly destroy tumors. Therefore, it is generally applied in combination with other treatments such as radiation, chemotherapy, radiochemotherapy, gene therapy, surgery, and immunotherapy. The primary mechanisms of action of hyperthermia against cancer are explained in the review to be related to the induction of apoptosis (programmed cell death), DNA damage, creation of reactive oxygen species, effects on the membrane potential of mitochondria (energy powerhouses of cells), and activation of heat shock proteins [8].

Another 2022 review explains that 59% of all cancer cases globally have been reported from the low-middle-income group countries with breast, cervix and head and neck cancers constituting one third of these cases [9]. The review affirms that the safety and benefit of hyperthermia for these types of cancer has been well documented in various clinical trials and meta-analyses (analyses of data from numerous clinical trials). It concludes that hyperthermia could be a potential low-cost game-changer if added to already existing therapies in these regions.

A 2014 review of the clinical data on hyperthermia states that hyperthermia has gained renewed interest in the medical community as a means to treat cancer due to its effects on immunity and tumor metabolism as well as having an important role as an adjunct therapy for standard of care treatments [4].** **The review details trials from Holland and Germany that demonstrate the ability of hyperthermia to prolong life expectancy and reduce recurrence of disease when combined with chemotherapy and radiation. It explains that the data from clinical trials support the use of hyperthermia for multiple cancer types such as cervix cancer, recurrent breast cancer, head and neck cancer, melanoma, sarcomas, liver cancer, glioblastoma and pancreatic cancer. However, the review also indicates that there are certain ongoing clinical and technical problems associated with hyperthermia that still need to be resolved through further research and development in order to improve treatment outcomes and mitigate side effects.

A 2020 clinical trial on breast cancer is a specific example of improved outcomes as a result of applying hyperthermia in conjunction with conventional treatments [10]. Prior to surgery, 200 women with stage IIB and IIIA breast cancer were given chemotherapy with hyperthermia or chemotherapy alone. The group who underwent chemotherapy combined with hyperthermia had higher overall 10-year survival rates.

A 2001 review of clinical trials on hyperthermia in combination with radiotherapy, chemotherapy or both, analyzed data from 2200 patients [11]. The trials were carried out on adult and pediatric patients with a wide variety of different solid tumor types such as melanoma, head and neck cancer, breast cancer, cancer of the gastrointestinal or urogenital tract, glioblastoma and sarcoma. The review cites growing clinical acceptance of hyperthermia as a result of comprehensive research, which provides a sound scientific basis for the application of hyperthermia in conjunction with conventional treatments. Technical advancements to achieve more targeted temperature increases in both superficial and deep-seated tumors is mentioned as an area of ongoing research (which still continues to this day) in order to improve the safety and efficacy of hyperthermia for local tumor control and improving relapse-free survival times [11].

Potential Applications of Hyperthermia

There are a variety of therapeutic applications for hyperthermia. The treatment is most commonly applied for the following types of cases:

• Deep-seated inoperable tumors
• Patients with health conditions that prevent surgery
• Small tumors near the surface of the skin
• Tumors located in a body cavity
• Advanced metastatic (widespread) cancers

Hyperthermia as a cancer treatment is not widely available in the USA. When it is used it is most often combined with radiation or chemotherapy for advanced cancers. It has been used clinically for the following types of cancers [12]:

• Appendix cancer
• Bladder cancer
• Brain cancer
• Breast cancer
• Cervical cancer
• Esophageal cancer
• Head and neck cancer
• Liver cancer
• Lung cancer
• Melanoma
• Mesothelioma
• Sarcoma
• Rectal cancer

Research shows that hyperthermia works synergistically to enhance the efficacy of chemotherapy and radiation [13]. It has been shown to be especially beneficial for tumors that can be targeted locally (such as cervical, head and neck cancer, melanoma and others). Hyperthermia can also provide systemic therapeutic effects when the whole body is heated. It activates the immune system and has been shown to have synergistic effects with immunotherapies [13].

There are three main clinical methods of administering hyperthermia, which depend on the location of the tumor, stage of the cancer, and the type of energy distribution technique [14].

• Local (for localized tumors)
• Regional (for progressive or deep-seated tumors)
• Whole-body (for widespread tumors)

Local hyperthermia is generally applied for relatively small tumors located close to or on the surface of the skin. It can also be applied within a body cavity such as the esophagus or rectum [14]. Microwaves, radio waves, or ultrasound are most frequently used to transfer heat to the tumors.

Regional (or partial) hyperthermia is applied to heat large parts of the body and is most commonly applied to treat advanced tumors in the pelvis, abdomen or thighs [14]. The procedure involves drawing the patient’s blood, heating it, and then pumping it back into the affected limb or organ, often in combination with anticancer drugs [14].

In whole body hyperthermia heat is applied throughout the entire body using either hot blankets, inductive loops or a thermal chamber [14]. The treatment raises core body temperature to at least 41 °C for several hours. Patients require deep sedation or general anesthesia to tolerate the therapy. It is most commonly applied for metastatic cancers [14].

Studies on the different approaches to hyperthermia treatment have reported that the therapy alone is not sufficient to destroy tumors completely, but can enhance the effects of anticancer drugs and make cancer cells more susceptible to treatment [14]. Despite an increasing number of studies on the mechanisms of hyperthermia many details still remain to be fully elucidated [1].

However, research does show that hyperthermia alone may help to inhibit tumor growth and prevent metastasis [1]. Blood vessels in tumors differ from normal tissues and assemble into a chaotic network of capillaries [1]. This results in a low oxygen environment at the tumor site. Mild temperatures (37°C to 42°C) cause vascular dilation, improve blood flow, and increase tumor oxygenation, which can reduce inflammation. At higher temperatures (above 42°C) blood vessels supplying the tumor are directly damaged by increased permeability [1]. This has been shown to inhibit tumor growth and metastasis [1]. Hyperthermia also induces heat shock protein synthesis, which interferes with telomere (DNA sequences related to cell preservation and life cycle) activity and indirectly promotes cancer cell apoptosis (programmed cell death) [1].

When hyperthermia is given in conjunction with chemotherapy it can lead to an overall enhancement of drug toxicity [1]. An artificial increase in temperature affects cell membrane structure and permeability, which in turn leads to increased uptake of chemotherapy agents [1]. Hyperthermia also increases the sensitivity of cancer cells to radiation [1]. Hypoxia (low oxygen environment) is well known to be related to radioresistance (resistance to radiation) [1]. Therefore, tumor oxygenation as a result of vascular dilation and increased blood flow enhances radiosensitivity of tumors [1].

The hypoxic state of the tumor microenvironment has been shown to suppress the immune system [1]. Using heat to reoxygenate a targeted tumor site can play an important role when coupled with immunotherapy and enhance its efficacy. Furthermore, elevated temperature can induce a systemic immune response and stimulate antitumor activity throughout the entire body [1]. Numerous studies have revealed that heat can activate cancer-killing immune cells such as macrophages, dendritic cells, and natural killer cells [1].

The selection of the most appropriate means to deliver heat to the tumor site is one of the most important and challenging issues in hyperthermia treatment [5]. Conventional hyperthermia uses many different energy sources (microwave, radiofrequency, laser, ultrasound and others). Wth standard hyperthermia methods it is difficult to target heat directly to tumors without energy dissipating into healthy tissues, which can lead to side effects. In recent times, nanotechnology has been introduced into hyperthermia treatment as a possible solution for these problems [5]. Nanoparticles are able to absorb heat energy from an external source and can be targeted to a specific tumor site [5]. This means that nanoparticle-mediated hyperthermia has the potential to induce localized thermal destruction while mitigating collateral damage to surrounding tissues [5].

Further research and development is still needed to better understand the potential of hyperthermia in cancer care and improve safety and efficacy of treatment approaches. However, it appears to be a promising adjunct therapy to enhance the effects of conventional treatments and may play a more significant role as a primary cancer treatment as methods of heat application advance.

Risks and Side Effects of Hyperthermia

Similarly to most cancer treatments and therapies there are certain side effects of hyperthermia. The potential side effects differ depending on the method of hyperthermia applied.

Local hyperthermia has the following potential risk and side effects [13]:

• Pain at the site of application
• Infection
• Bleeding
• Blood clots
• Swelling
• Blistering
• Damage to skin, muscles, and nerves

Depending on the level of heat exposure regional and whole-body hyperthermia come with the following potential risks and side effects [13]:

• Nausea
• Vomiting
• Diarrhea

In very rare cases regional and whole-body hyperthermia can also result in [13]:

• Heart problems
• Blood vessel issues
• Major organ problems

If you are considering hyperthermia treatment it is important to speak to your healthcare provider to better understand possible risks and side effects.