Hyperthermia: The Last Hope Therapy
To understand how hyperthermia is employed nowadays, it’s crucial to realize the extensive history of such treatment. Next, it’s important to outline this biological rationale of hyperthermia as well as debate how EM energy and other techniques can elevate temperature inside the organism. It is possible to implement hyperthermia alone or together with other methods such as radiation therapy, chemical therapy, surgical treatment, immunotherapy, and others. Clinical hyperthermia divides in three major categories:
- local hyperthermia
- regional hyperthermia
- entire-body hyperthermia
Due to the individual characteristics of each type of therapy, different kinds of heating systems have developed.
The word “hyperthermia” consists of two Greek terms: -hyper- (over, beyond) and -therme- (hot). It indicates a rise of temperature of the body in order to reach an accurate therapeutic effect. Although hyperthermia is believed to be one of the oldest types of therapy, mainstream medicine has neglected this method for many years. Among the principal elements which have impeded the clinical benefit of hyperthermia are the reproducibility of heat deposition in the tumour mass as well as the difficulty of measuring the tumour temperature and its surrounding tissues.
The heat always had sacred meaning. It was connected to the extraordinary healing abilities of the Sun. The heat application to cure various illnesses (including tumors) has been typical in multiple cultures from the beginning of human history. The first widely known uses of heat therapy was performed by an ancient Egyptian haruspex named Imhotep (2658–2600 BC). The curative power of hyperthermia therapy was also cited during the early civilizations of Egypt. One of the recommendations for the sick were burning-hot sand baths in the desert.
Hyperthermia is a technique of dealing with cancer which has an extended history. Lots of Greek and Roman physicians thought that if they were able to simply regulate the temperature, they could treat all diseases. It even included tumors because the pathology of cancer growth had been represented in the Greek literature. Parmenides (530–460 BC), a Greek practitioner and theorist said, “Give me a chance to create a fever and I will cure any disease”. Physicians from ancient Greece began to use this therapeutic method and called it “overheating” (in Greek, hyperthermia). Such approach was approved by Hippocrates (450–360 BC), a Greek thinker and physician who is regarded as the “father of medicine”. Furthermore, Hippocrates worked with heat to cure breast tumours successfully. It is also worth mentioning that localized and systemic procedure of hyperthermia were known in ancient China and India.
Belief in the healing effect of heating was also described by Celsus (20–40 ad), a writer from Rome. He illustrated hot bathing as an instrument in the treatment of different illnesses. In the splendour of the Roman Empire, hot bathing constituted a habit, often with complete facilities involving the localized or general application of steam and dry heat. Today, sauna baths in Finland, hot baths in Japan, Native American ceremonial sweat lodges, and therapeutic hot springs in Europe, Iceland, and North America have been noted to stimulate the immunity, increase blood flow and enriching tissue with oxygen, relax muscle tension, and increase stimulus conduction of nerve fibres.
Early research history
In the eighteenth and nineteenth centuries, hyperthermia treatment became more evidence-based. It was noted that whenever patients with cancer had a severe fever because of erysipelas or malaria, their tumours began to grow smaller. Carl D. W. Busch (1826–1881), a surgeon from Germany, was the one who published an article on hyperthermia in 1865. The piece was about one 42-year-old person who had the sarcoma on the head. The woman got sick with erysipelas, which caused a fever and afterwards the tumour got cured. Later, Carl Busch intentionally infected several patients with erysipelas to treat tumours. In 1893, William B. Coley (1852–1926) reported 38 persons with progressing confirmed cancer suffering erysipelas with high fever; in 12 of them, tumours had disappeared, 19 had displayed an improvement; in two of ten patients with locally advanced sarcomas treated by Coley, complete remission had occurred. Coley himself has never singled out the fiver in the capacity of the key mechanism for antitumor effect. He considered it to be the effect of its vaccine complex.
Nevertheless, he repeatedly declared that the more severe and critical the fever, the greater the curative effect was. In 1890, Coley developed a microorganism that caused standard erysipelas with the typical fever. When radiotherapy was introduced in the XX century, and the clinicians and researchers started blending it with heat, they discovered that hyperthermia increased sensitivity of tumour to radiation treatment. In 1912, Muller described 100 patients treated with the X-ray and hyperthermia.
The next years were important for the contemporary use of the method of hyperthermia. Later, the breakthrough of blending ionizing radiation and the heat stimulated a significant growth in the amount of both theoretical and clinical research from the 1950s till the present time.
After 1960, the modern phase of hyperthermia progress as a distinct treatment modality had started. In 1950, Gessler announced the successful destruction of spontaneous breast tumours in mice by hyperthermia using microwaves (2,450 MHz) without significant harm to the animals.
The real establishment of the recent oncological hyperthermia has been laid by a Cleveland surgeon and mammary cancer specialist, George Crile Jr. (1908–1993), who in 1962 made a famous breakthrough, expressing that prolonged heating of some tumours up to 43–50C might selectively abolish it without harming the healthy bordering tissues. Remarkably, all the important hyperthermia technologies had been invented between 1975 and 1985, exactly at the time when a biophysical base of treatment wasn’t entirely set. In Japan, the research on hyperthermia took its place in 1979. Japan became a world leader with substantial government support and hundreds of hyperthermia systems installed in the next few years.
In 1976–1977, the growth in all major technologies for intensive heating had started.
In 1987, by mixing hyperthermia with bioelectromagnetism and human physiology, the latest modality of the fight against cancer named “oncothermia” was initiated by the Budapest Science University. This interest has followed a course that is usual for a new type of treatment. In 1985, hyperthermia was considered a promising method in oncology. It was often called the potential fourth primary treatment method in oncology, after surgery, chemotherapy, and radiotherapy. Two key articles, published in the mid-1980s, attracted attention to the opportunity to assess the efficacy of cell killing with heat. These papers formed the first concepts for thermal dosimetry. They denoted that numerous cell killings could occur if cells or tissues were heated to >42 C for one hour or more.
Though hyperthermia had remained a “hot topic” in scientific journals and among practical oncologists and radiologists, there was no substantial progress in its technologies after 1985 despite significant activities. During the 1990s to the 2000s, several trial clinical studies using various treatment modalities were launched worldwide with mixed results, both positive and negative. Overall, enthusiasm for hyperthermia decreased significantly in the mid- to late-1990s, partly due to the perceived difficulties in achieving adequate treatment as defined by the need to kill cells directly by heating. The problem that was faced by the hyperthermia community at that juncture was unrealistic thermal goals because of the lack of adequate equipment for delivering thermal treatment and the inability to measure the treatment provided. The combination of the above problems is still a challenge to the design and implementation of successful hyperthermia clinical trials.
Today, there appears to be a gradual but cautious interest, thanks to several investigations demonstrating that the improvements in treatment outcome by adjuvant hyperthermia can be very substantial, provided that adequate heating procedures are used. After more than 70 years of serious development, having more clinical trials and publications than any modern popular pharmaceutical, hyperthermia is still not accepted in any oncology branch. One or two occasional inclusions in one or two guidelines as “the last hope therapy” with many controversies are the demonstrative result of this development. The clinical exploitation of hyperthermia was and still is hampered by technical limitations and the high degree of interdependency between technology, physiology, biology, and practice.