Essay: Hyperthermia therapy and tumor treating field therapy for cancer

Alternative Therapies to Cancer
Abstract
When people hear the word cancer, many immediately think about the different types of treatment such as chemotherapy, radiation, and surgery. In today’s day and age, there are many other treatment options out there that range beyond traditional types of therapy. As new technology is constantly being developed, it is no surprise that there are many different types of treatments options out there for patients. In this report, I will review two therapies that are alternatives to the most common treatments for cancer. One of these therapies uses directed heat to kill cancer cells and the other therapy uses electric fields to disrupt cancer cells, in turn killing them as well. Many of these new treatments work in combination with chemotherapy or radiation but drastically increase overall survival comparatively. In my report I will focus on the two alternative cancer treatment options I mentioned and how they are currently used, how they work, their history, their side effects, their effectiveness, their cost, and their availability.
Hyperthermia Therapy
Hyperthermia therapy, also called thermal therapy or thermotherapy is the use of heat to damage and kill cancer cells (Cancer.gov). The high temperatures are thought to be able to shrink tumors with minimal damage to normal tissues. The mechanism of action is that high temperatures stop the cancer cell’s ability to repair DNA damage from radiation. The high temperatures specifically disable repair enzymes in the cell, cause cells to release heat shock proteins, and cause the cancer cells to be more sensitive to chemotherapy or radiation. The benefit of cells releasing heat shock proteins is that they cause a person’s immune system to be stimulated and causes their immune system to fight against the cancer cells. By disabling repair enzymes in the cell, the cancer cells then die effectively causing the tumor to shrink (Texas Oncology).
History
The use of heat to increase immunity and health has existed since the ancient times. The word hyperthermia can be traced back to 3000B.C. where the word was coined from the combination of two Greek words, hyper(rise) and therme (heat). In their definition it was the raising of body temperature to attain a therapeutic effect. Earlier than that, seen in the Edwin Smith Papyrus (from around 1700B.C.), an Egyptian named Imhotep used fire in the treatment of breast cancer, using fire to burn the cancerous cells. Ancient India and China also used hyperthermia for its therapeutic effects. Later on, in ancient Greece and Rome, the Greek philosopher Parmenides believed in the use of fever, whole body hyperthermia, to cure disease. Another Greek philosopher, Hippocrates was also seen successfully treating breast cancer using heat. Later on, in the year 1886, the first paper describing the use of heat to cause tumor regression was published by a German surgeon named Carl D.W. Busch. That event caused others to become interested in the use of hypothermia and inducing fever in patients to treat cancer. In 1891, American surgeon William Coley also documented the remission of cancer with fever and became known as “the father of the modern use of hyperthermia and immunotherapy against cancer” (Gas 2011). Other doctors and researchers tried other methods, like removing blood and heating it, some found success and others found death.
Once radiation was discovered in 1895, the use of hyperthermia in cancer treatment decreased also due to underdeveloped methods of treatment and lack of promising results. Then things changed when G. Schwarz in 1910 and Müeller in 1912, tried combining hyperthermia treatment with radiation and received good therapeutic results. Due to funds being diverted to the war effort, interest in hyperthermia therapy was dismissed until 1962 when another American surgeon named George W. Crile Jr. discovered that raising tumors to 42-50 degrees Celsius “selectively destroyed them without damaging the healthy tissue” (Gas 2011). The discovery of microwave heating techniques and the application of it in medicine changed how hyperthermia therapy was implemented and used (Gas 2011). Since then, there have been few trials and not much progress but regardless, hyperthermia therapy is still regarded as a treatment that works.
Treatment
Hyperthermia therapy has different treatment methods depending on where the tumor is in the body and how big the tumor is. The different treatment types are local, regional, and whole body. Local hyperthermia is where heat is applied directly to a tumor or a small area and can be applied directly on the target area or can be applied through probes placed in the specific area. Regional hyperthermia is where heat is applied to a large tissue area. Whole body hypothermia is when a person’s body temperature is raised almost as if they have a fever. For whole body treatment, “blankets, warm water, or a heated chamber are used to warm the person’s body” (Gersten 2017). In the other cases, heat is created through using either microwaves, radiofrequency, and/or ultrasound. Radiofrequency ablation, RFA, is used for local treatment and is the most common type of thermal energy, using “high energy radio waves for treatment” (Cancer.org). In RFA, a needle-like probe is inserted into the tumor “sends radio wave energy directly into the tumor”. RFA is most commonly used in cancer cases where tumors cannot be taken out with surgery, for example, liver, kidney, and lung tumors (Gersten 2017). The temperature used is around 106-113 degrees Fahrenheit and is administered by a device called the BSD-500 (Excellus BCBS). A surface applicator is applied to the tumor and the area is heated for around an hour. Usually hyperthermia is done within an hour of radiation (UCSF). Side effects sometimes occur and include burns, blisters, discomfort, or pain (Cancer.org).
According to Excellus BlueCross BlueShield health insurance, their medical policy states that “based upon our criteria and assessment of peer reviewed literature, superficial hyperthermia has been medically proven to be effective and therefore, medically appropriate when used in combination with radiation therapy for the treatment of patients with the following: Superficially recurrent melanoma; chest wall recurrence of breast cancer; or recurrent cervical lymph nodes from head and neck cancer” (Excellus). Although this insurance approves of certain types of hyperthermia, others are only considered investigational to them. The treatments that are considered investigational are interstitial hyperthermia, regional hyperthermia, regional perfusion hyperthermia, and whole-body hyperthermia. The reason the Excellus BlueCross BlueShield and the FDA have not approved other types of hyperthermia treatment is because studies do not have enough patients, do not have a standard technique, are not random or controlled, and do not have long term results. Currently the Food and Drug Administration (FDA) has approved hyperthermia in the treatment of solid surface and subsurface malignant tumors that are recurrent or progressive despite regular treatment (Excellus). Medicare approves hyperthermia treatment when used with radiation for primary or metastatic cutaneous or subcutaneous superficial malignancies and it is not covered when used alone or with chemotherapy (Center for Medicare and Medicaid Services). Although not all treatments are FDA approved, University of California San Francisco uses “multi-modality hyperthermia” meaning that they customize the treatment to each patient’s cancer, including combining chemotherapy and hyperthermia (UCSF).
Cost of treatment is something that is very important to cancer treatment, as if something is too expensive, it limits the availability of treatment. Based on research on line, there are no current prices for the cost of hyperthermia treatment, but we can infer from other countries and the past on what the cost might be like now. Back in 1994 a “hyperthermia project” was done at the University of Turin in Italy. When the cost of treatment is converted to USD, the cost per treatment was around $2,676 but that was back in 1994(Gabriele 1994). When accounting for inflation, the cost per treatment would now be $68,038.52.
Prognosis
When hyperthermia therapy is used in conjunction with radiation therapy, in the treatment of solid surface and subsurface malignant tumors that are not responding well to normal treatment, the response rate is around 70% compared to a response of just 35% for radiation alone (Excellus BCBS).
Tumor Treating Field Therapy
Another therapy that is not well known is tumor treating field (TTF) therapy. Tumor treating field therapy is the use of electrical fields to disrupt rapidly dividing cancerous cells (Hopkins Medicine). The electric field acts on charged proteins, such as tubulin and septin, in the cells that are important for mitosis, cell division (Novocure). It specifically stops the cell from forming chains that separate genetic material in the cell’s nucleus and the correct positioning of these charged proteins before cell division (Hopkins Medicine). When cells cannot divide normally, they go through a process called apoptosis, cell death.
History
The conception of tumor treating field therapy started with an Israeli man named Dr. Yoram Palti. He wanted to explore how electric fields can treat tumors and explored this idea in his basement in 2000 and soon opened up a research center in Haifa, Israel in 2002. After coming up with the idea and forming his company, Novocure, the first pilot trial was performed in Prague, Czech Republic in 2004. After initial promise, trials were then started across the United States, European Union, and Israel in 2006 to test TTF versus chemotherapy in the treatment of recurrent glioblastoma. Another trial started in 2009 and moved to focus on and treat newly diagnosed glioblastomas. This new trial treated patients who had already received surgery and radiation with TTF and also included using temozolomide, a chemotherapy drug used for treating glioblastoma multiforme (The Oncologist). When the first trial proved TTF to be a successful treatment in 2011, the FDA approved TTF under the name “Optune” for the treatment of recurrent glioblastoma. When the 2009 trial proved even better results, the FDA approved “Optune” to treat newly diagnosed glioblastoma. Since then, Novocure has created even more trials for different types of cancer and has even been able to optimize their system to create a smaller therapy delivering device. At this moment they have trials for brain metastases, non-small cell lung cancer, pancreatic cancer, ovarian cancer, liver cancer, and mesothelioma. Not only do they currently have ongoing clinical trials for many different cancers, they even have pre-clinical trials set for a very extensive list of other serious types of cancer like breast cancer, cervical cancer, and malignant melanoma to name a few. The Optune treatment can be found in the United States, Germany, Austria, Switzerland, Israel, and Japan.
Treatment
The biggest use currently for TTF is in the treatment of glioblastoma multiforme. Glioblastoma multiforme, also abbreviated GBM are automatically considered Grade IV tumors as a majority of the tumor cells are dividing regularly. The tumor is made up of abnormal astrocytic cells and invades regions of the brain, sometimes even spreading to the opposite side of the brain through the corpus collosum, connective fibers of the brain. Many times, these tumors appear de novo, meaning that there was never a precuring growth. Symptoms of the tumor usually appear abruptly due to excess fluid in the brain causing further swelling. Neurological symptoms may occur as well depending on where the tumor is located in the brain. The treatment of GBM is very tricky as some cells respond well and others not at all. On top of that, when looking at the surgical removal of a GBM, things get even more complicated as the tumor has tentacle like diffusions that invade the brain, making it very difficult to remove (American Brain Tumor Association). When looking at the treatment of GBM, it is usually resistant to standard chemotherapy, so patients usually have a biopsy or extensive surgery done to try and remove parts or all of the tumor. Almost all GMB recur and so the next treatment steps depend on many different factors like the condition of the patient and “the extent and location of the recurrence” (Emerging Technology Evidence Report 2015). TTF works well in this specific type of cancer as the cancerous cells are the ones that are dividing most in the central nervous system, so they are the cells that are mostly targeted.
The way the treatment is given is through “small transducers that are attached to their head with adhesive bandages” (Hopkins Medicine). The whole contraption consists of wires, connected to transducers, connected to batteries and in total is around the size of a book (Hopkins Medicine). This allows this treatment to be portable and continuous, only unplugging the device for short amounts of time when bathing. The only downside to this treatment is that in order to use this treatment, one must shave their hair. TTF therapy is often used in combination with the chemotherapeutic drug temozolomide, sometimes abbreviated TMZ.
The least common side effects, seen in 10% or less of patients, of the treatment when in combination with temozolomide are “low blood platelet count, nausea, constipation, vomiting, fatigue, scalp irritation from device use, headache, convulsions, and depression”. The most common side effects of just using TTF are “scalp irritation from device use and headache”. There are also adverse reactions seen in relation to using the device such as “scalp irritation from device use, headache, malaise, muscle twitching, fall and skin ulcer” (Novocure).
The cost of TTF therapy, specifically Optune, runs at $21,000 a month. On average, patients use TTF therapy for 4.1 months and so the cost falls around $86,000. According to the Emerging Technology Evidence Report, currently, Medicare does not have a determination on the national coverage of TTF therapy, so it is up to the discretion of local Medicare carriers. Also, according to the report, out of eleven private insurance companies in the United States, one covers TTF therapy, seven deny coverage and consider the treatment “investigational”, and three have no policy about it. According to Novocure, the company that owns the device, many insurance companies have provided coverage of the therapy by using a case-by-case system, determined by the medical necessity of treatment. The Musella Foundation for Brain Tumor Research and Information created an assistance program from patients needing TTF therapy for recurrent GBM. Also, certain patients who live in the United States and meet specific income conditions can receive up to $5,000 per year for the treatment (ECRI Institute 2016). According to the New York Times, Novocure offers the treatment for free for patients without health coverage (Grady 2014).
Prognosis
When patients used Optune (TTF therapy) for 12 hours or more a day and also took TMZ during the same period, 86% of patients increased their survival rate compared to just taking TMZ alone. The more compliant patients were with using the device, the better their outcome was. In order to get the best results and maximal survival benefit, patients should aim to use the device for at least 18 hours a day. For patients who had compliance over 90%, their median survival was 24.9 months and their 5-year survival rate was 29.3% (Ram 2017). When dealing with glioblastoma (GBM), the median overall survival rate is around 15 months and the rate of 5-year survival is estimated to be 5% (Tykocki 2018).
Conclusion
In conclusion, hyperthermia therapy and tumor treating field therapy come from very different scientific concepts, but both aim to kill cancer cells and save cancer patient’s lives. Hyperthermia treatment was created after witnessing patients with high fevers achieve remission and tumor treating field therapy was created after someone thought of the idea. Although hyperthermia therapy has been since the ancient times, not much has changed with the process since the early 1900’s and it is still used in the same fashion today, if used at all. Even though in addition with radiation, hyperthermia therapy shows therapeutic results, very few cancer treatment centers boast about their use of this specific therapy. It is covered by Medicare and some insurance companies though, so we can assume it is still used today. On the other hand, Tumor Treating Fields have only recently been discovered and on the market for doctors to prescribe and for patients to use. Since discovering the success of the treatment, many clinical and preclinical trials are in the works and they will hopefully achieve promising results. Already, the amount of time it has added for patients with GBM is lifechanging. This technology is one of the first to change the life expectancy for GBM in a very long time. Also, it has very little reported side effects for everything that it can do. There are many benefits to this treatment and very few, if any drawbacks, except maybe that it has to be worn for many hours of the day. Overall, this therapy is extremely promising and all who have the opportunity to use this type of therapy should. Hopefully many more lives can be saved by this innovation.
This report may not include everything about these treatments and there are many other alternative treatments out there, but I decided to focus on these two as they seemed the most interesting to me.