The FDA has approved hyperthermia in combination with radiation therapy for the palliative management of certain solid surface and subsurface malignant tumors (i.e. melanoma, squamous or basal cell tumors, adenocarcinoma, or sarcoma) that are progressive or recurrent despite conventional radiation therapy. Hyperthermia requires special equipment and a doctor and treatment team who are skilled in using it.
History
Hyperthermia not a new treatment for cancer. Treating cancer with the use of heat may have been recorded back as far as 1600 BC in the Edwin Smith papyrus, and Hippocrates claimed the ability to treat cancers with heat was what distinguished curable from incurable cancers.
A century ago, physicians were familiar with a phenomenon in which cancers regressed or sometimes went away completely. This improvement and sometimes complete disappearance of a tumor was often seen following an infection accompanied by a high fever (often erysipelas) or following injections of killed cultures of streptococci or a type of bacillus. It isn’t completely clear what led to the spontaneous remission of cancer in these cases.
Uses
Hyperthermia—either local, regional, or whole-body—can be administered alone or in combination with chemotherapy, radiation, or immunotherapy for a number of different cancers.
Types
Methods are frequently broken down into those that are:
Local, for tumors near the surface of the body or that can be reached through probesRegionalWhole-body (usually for metastatic tumors)
How It Works
The mechanism behind hyperthermia use for cancer treatment differs with each method.
High temperatures: Used to kill cancer cells. Mild temperatures: Used to sensitize cancer cells to other treatments or enhance the ability of these treatments to reach cancer cells.
In addition to direct damage, hyperthermia can cause damage at the molecular level such as:
Disrupting DNA repair in cancer cellsReleasing certain chemicalsActivating an immune response to a cancer
Ablation of Cancer Cells
With local therapies such as radiofrequency ablation, high temperatures are used to directly damage cancer cells and surrounding tissues.
Cancer cells differ from normal cells. These differences could result in different responses to heat. In addition, heating can inhibit the process of tumor growth (cell division) as well as the ability of cancer cells to spread (metastasize).
Enhancement of Treatments
Hyperthermia may enhance the cell-killing effect of treatments such as:
Chemotherapy Radiation therapy Immunotherapy
Hyperthermia may increase blood flow to a tumor so that it is more susceptible to the effects of these treatments, but there are other effects that can be specific to the treatment type.
When hyperthermia is used with chemotherapy or radiation therapy, it is used within one hour of treatment. An exception is with regional hyperthermia in which they are used at the same time.
After treatment with hyperthermia, there is a period of transient insensitivity to the effects of hyperthermia. For this reason, hyperthermia is used once or twice weekly with radiation at the most.
Chemotherapy
Hyperthermia can enhance the effect of chemotherapy, and this may be:
AdditiveSynergistic (work better than would be expected by the combination of hyperthermia and chemotherapy alone)Act in ways that are independent of the interaction
An increase in temperature surrounding a tumor can alter the lipids in cancer cells so that chemotherapy drugs can gain access more easily. With some drugs—such as cisplatin—this results in a synergistic effect. With others—such as carboplatin and oxaliplatin—the effect is additive.
Radiation Therapy
Hyperthermia may increase the sensitivity of cancer cells to ionizing radiation in a few ways.
These include:
Increased sensitivity to radiation: Potentially due to increased blood flow that results from mildly elevated temperatures, but not high temperatures. Reduced ability of cancer cell repair: This is caused by changes in DNA repair proteins due to heat. Induced production of heat shock proteins: These proteins (in a mechanism that interferes with the activity of an enzyme called telomerase) promote the death of the cells.
The effects of hyperthermia combined with radiation vary depending on cancer type and stage, but overall, it could improve the effectiveness of radiation by up to 50%.
Hyperthermia may have a role in the treatment of recurrent cancers. The effect of radiation therapy is often limited due to relative hypoxia (low oxygen) in tissues, and this has been a significant problem with recurrent tumors. The combination of hyperthermia and radiation may allow for the treatment of cancers that have been previously treated with radiation but have recurred.
Immunotherapy
Since hypoxia surrounding a tumor microenvironment appears to play a role in the relative immunosuppressive state of the tissue microenvironment, it’s thought that hyperthermia could—through increased blood flow—improve the effectiveness of immunotherapy drugs such as checkpoint inhibitors.
While studies looking at the effectiveness of combining hyperthermia with immunotherapy have not yet been done, preclinical studies suggest that the combination could enhance the effect of immunotherapy at all eight steps in the cancer-immunotherapy cycle.
Inhibiting the Repair of Damaged Cancer Cells
Cells, including cancer cells, produce proteins that work to repair damaged DNA. When cancer cells are unable to repair the damage caused by treatment, they are more likely to die.
Hyperthermia is thought to impair DNA repair enzymes within cells, thus interfering with this repair.
Enhancing the Immune System and Reducing Immune Suppression
Hyperthermia is thought to impact the immune system response to cancer by:
Enhancing the body’s immune response to cancer cellsReducing immune suppressionReducing the immune escape of cancer
When combined with radiation, activation of immune response appears to involve both the innate immune system and adaptive immune system, affecting cells ranging from T cells, to natural killer cells, to macrophages, and more.
Local Hyperthermia
Local hyperthermia involves the use of high heat is applied to a small, local area of tissue to kill cancer cells and the blood vessels that supply a tumor. While it varies, temperatures of 103 to 110 degrees Fahrenheit are most often applied for a period of 45 to 90 minutes.
Local hyperthermia leaves behind scar tissue. On conventional scans such as CT or MRI, this can sometimes be difficult to distinguish from an actively growing tumor. Positron emission tomography (PET scan) is a functional test that can often make this distinction.
The heat may take the form of:
Radiofrequency ablation (high energy radio waves): the most common methodMicrowavesUltrasound (high intensity focused ultrasound)Others
Local hyperthermia may be used in different ways:
Externally: To treat tumors near the skin surface (less than 3 to 4 inches below the surface). Intraluminally: To treat deeper regions of the body that are accessible through special techniques, such as the esophagus during an endoscopy. Interstitially: To treat tumors that are deeper in the body but can be reached by a probe to introduce a heat source. For example, radiofrequency ablation may be used via a needle inserted into the tumor to treat cancers of the brain, lung, liver, or kidney. The probe may be kept in place for around 30 minutes.
Methods of treatment vary, but with surface hyperthermia, a surface applicator is usually applied directly over the tumor.
Regional Hyperthermia
In contrast to local hyperthermia, regional hyperthermia involves the treatment of a larger area, for example, part of all of an organ or a limb, such as an arm or leg.
Regional hyperthermia may be used:
Externally: Treatment of a deeper area than local hyperthermia. Regionally (isolation perfusion): With this technique, blood from an area such as the leg may be removed, heated, and reintroduced along with chemotherapy to treat cancers such as sarcomas and melanomas. Deep tissue: An example of deep tissue regional hyperthermia may be used in the treatment bladder cancer. The device is placed over the bladder, and microwave or radiofrequency waves used to heat the region.
Whole Body Hyperthermia
Whole body hyperthermia is used primarily for treating metastatic cancers.
The goal is to heat the entire body in order to raise body temperature to 107 to 108 degrees Fahrenheit for a period of 90 minutes or more.
This may be done with the use of:
Hot water blanketsThermal chambers that resemble incubators used for babiesImmersion in warm water
Hyperthermia in Combination Therapy
There are many combinations of hyperthermia, chemotherapy, and radiation that have been used or are currently being studied in clinical trials.
Chemotherapy
Hyperthermia along with neoadjuvant chemotherapy (chemotherapy before surgery) has been used to treat people who have high-risk soft-tissue sarcomas and has been compared with the use of chemotherapy alone.
In a 2018 study, the combination of hyperthermia and chemotherapy resulted in improved survival as well as progression-free survival for people with soft tissue sarcomas compared with those who received chemotherapy alone.
Radiation
When cancer spreads to bones (bone metastases) people often experience severe pain.
Researchers compared the use of radiation therapy alone to treat bone metastases with that of radiation therapy plus hyperthermia (hyperthermia applied within an hour of the radiation). It was found that those who received the combination therapy had almost twice the response to treatment (reduction in pain) as those who received radiation therapy alone.
Hyperthermia in combination with radiation may be particularly helpful in some settings. A 2019 review of studies looking at the use of hyperthermia combined with radiation therapy for recurrent breast cancer found that the combination appeared to influence the complete response, the duration of responses, and overall survival compared with the use of radiation therapy alone. Similar benefits have been noted in studies looking at melanoma, sarcoma, and cervical cancer.
Combination with Supportive Care in Refractory Cancer
A 2020 study showed promise for the use of hyperthermia for those with the most advanced tumors.
A combination of hyperthermia (modulated electrohyperthermia three times weekly for 25 sessions) plus intravenous vitamin C was given to a group of people with advanced, refractory non-small cell lung cancer. Though the study was small, it did show a controlled rate of 42.9% in the treatment group compared with 16.7% in a group that received the best supportive care alone.
Quality of life was also better in the treatment group. The study primarily demonstrated safety in using hyperthermia in this setting and did raise the hope for further studies looking for methods to improve the quality of life for those with advanced cancers.
Risks and Side Effects
The risks and side effects of hyperthermia tend to be relatively mild, especially compared with the side effects of many other cancer treatments.
The risks will vary depending on the:
The specific type of hyperthermiaDuration of useThe specific delivery system used
Adverse effects of local hyperthermia can include burns and pain associated with burns. With regional hyperthermia, there have been some reports of serious muscle necrosis (death of muscle) and subcutaneous fat which required surgery, but this is uncommon.
The risks of whole-body hyperthermia are similar to those expected with a significantly elevated body temperature and may include:
Feeling hotFatigueDiminished sweating due to rapid temperature elevation
More serious conditions may include:
DehydrationHeat exhaustionHeatstroke
Severe symptoms may be more common in people with certain underlying health conditions. Since high temperatures can be damaging to the peripheral nervous system, it should not be used for people who have neurodegenerative conditions such as multiple sclerosis.
Both regional and whole-body hyperthermia may also result in:
NauseaVomitingDiarrhea
More involved techniques—such as regional hyperthermia in which the blood is removed from a limb and warmed—carries risks related to perfusions, such as blood clots and more.
Limitations
Some limitations of hyperthermia include:
Challenges accurately measuring and maintaining the ideal temperature within a tumor. Limited availability, since the full range of hyperthermia options is offered at relatively few cancer centers across the country. Strict eligibility criteria for clinical trials. Varied scenarios for insurance coverage.
A Word From Verywell
Hyperthermia might be a promising way to improve cancer treatment, but it is largely an experimental technique at this time. The National Cancer Center Network recommends that the use of hyperthermia be limited to treatment centers with appropriate training, expertise, and equipment. Many clinical trials of hyperthermia are being done to better understand and improve this technique. Researchers continue to look at how hyperthermia is best used along with other cancer treatments to improve outcomes.
