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A history of hyperthermia therapy (part I)

Hyperthermia, Uncategorized

In the first of three articles exploring the history of hyperthermia as a medical treatment, Johannesburg-based urologist Dr Steven Cornish delves back into antiquity to its origins and explores developments including thermal therapy combined with radiotherapy and with early chemotherapy

“Hyperthermia” comes from “hyper”, meaning rise, and “thermia”, meaning heat. The history of thermal therapy lies back in antiquity and it has a chequered timeline, as will be seen from this article. Its greatest period of adoption was during the 20th century with a decline at the end of the century due to the appearance unfavourable data, but in the second decade of the 21st century it is enjoying somewhat of a renaissance, specifically as it relates to regional therapy being augmented by hyperthermia.

From around 2655 BC, Imhotep – an architect, high priest and physician of the Old Kingdom – started using fire drills to treat breast cancer, a form of treatment that had nothing to do with elevating the body temperature but relied on local heat to kill cancer cells. Recorded in the famous Edwin-Smith papyrus, discovered in 1862 outside Luxor and the oldest papyrus of its kind in the world, this presents a rational and scientific approach to medicine in ancient Egypt – here, possibly for the first time, medicine and magic did not conflict. The papyrus is actually considered to be a copy of a more ancient text possibly written by Imhotep himself, who is also attributed with using infection to fight cancer by infecting a tumour with a poultice before cutting into the tumour – the first instance of immunotherapy.

“Give me the power to produce fever and I will cure all disease”

Parmenides, pre-Socratic Greek philospher

Fever was understood by ancient civilisations to be the hallmark of disease, induced by evil spirits. From what we can tell from the records, the Greeks were the first to believe in the beneficial effects of fever, giving heat a holy or sacral meaning associated with the healing powers of the sun. Ancient Greek philosophy attributed fire to the highest level of intelligence and freedom, with mud baths from natural thermal springs and hot air from volcanic caves employed in remedies. These systemic treatments are known to have been used by Ancients in China and India as well.

The Ancient Greeks believed that knowing how to control body temperature would allow them to cure all diseases – as Parmenides stated in the fifth century BC, “Give me the power to produce fever and I will cure all disease.” Hippocrates (460-370 BC), the father of medicine, believed that disease was incurable if it could not be remedied by heat, and the Greeks would use heat when surgery or traditional therapies had failed. In the words of Hippocrates, who is documented as using heat to cure breast cancer, “What medicines do not heal, the lance will; what the lance does not heal, fire will.” (Interestingly, Hippocrates described the side effects of heat therapy as including weakness, neurological changes, haemorrhage, and death – all adverse events that are similar to what is seen today with whole-body hyperthermic treatment.)

From the Greeks, the mantel of modern medicine was passed on to the Romans. The Roman author Celsus (25 BC-45 AD) wrote the first systematic treatise on medicine, De Medicina, in which he described hot baths as a curative modality of various diseases, including facilities for the application of dry or humid heat applied locally or generally, to treat various diseases.

In the Middle Ages, there was another surge of interest in the medical fields, including the use of hyperthermia. Instruments were designed and shaped for the direct application of heat to kill tumours or cauterise bleeding, albeit without the benefit of adequate anaesthesia. One can only imagine the pain suffered by victims of tumours who were lucky enough to be treated by a man of medicine.

The origins of cancer immunotherapy

In the Victorian era, progress for thermal therapy commenced along a scientific front for the first time. In 1866, Carl Busch published a landmark paper describing how a patient with a facial sarcoma fell ill after surgery with erysipelas and experienced high temperatures which led to tumour regression. This was the first paper to describe how high temperatures can selectively kill cancer cells but not healthy cells.

In 1890, an athletic 17-year-old, Elisabeth Dashiell – a close friend of John D Rockefeller – had just returned from exploring Alaska, where she had injured her hand in what seemed an inconsequential accident. Elisabeth chose to see a young, innovative surgeon, William Coley (1862–1936), in his new practice in New York City. Having recently emerged from Harvard Medical School, he was making a name for himself in the city’s surgery world. Elisabeth’s hand was not healing and had become swollen and naggingly painful. Dr Coley diagnosed a highly aggressive round cell sarcoma, and despite radical surgery, the disease rapidly progressed. After immense suffering, Elizabeth sadly died a few months later. But her case was to propel the career of Coley forward and have far-reaching effects on cancer research and American philanthropy. Rockefeller and Coley began a lifelong friendship, with Rockefeller pouring money into medical research and founding The Rockefeller University in New York City, while Coley embarked on a journey to develop the first immunological cancer treatment, thereby founding the field of cancer immunotherapy.

Coley began by investigating all past sarcoma patients at New York Cancer Hospital (now Memorial Sloan-Kettering). One was 31-year-old Fred Stein, who had had a round cell sarcoma resected five times from his neck and was considered an inoperable hopeless case. Then Stein contracted a severe erysipelas infection of his head and neck caused by Streptococcus pyogenes, accompanied by a raging fever. A second attack followed two weeks later. Thereafter, the sarcoma completely resolved. Coley found Stein seven years afterwards enjoying excellent health, with only a scar below his left ear to show where the inoperable sarcoma had been.

Stein contracted a severe erysipelas infection of his head and neck caused by Streptococcus pyogenes, accompanied by a raging fever. A second attack followed two weeks later. Thereafter, the sarcoma completely resolved

Trawling the available literature, Coley discovered 38 reports of cancer patients with accidental or iatrogenic feverish erysipelas. In 12, the sarcoma or carcinoma had completely disappeared, while the others had substantially improved.

His next patient, Zola, had a tonsillar tumour the size of a chicken’s egg almost completely obstructing his pharynx and had been given a few weeks to live. Coley injected S pyogenes to minimal effect; erysipelas was not induced. He then obtained a more virulent strain, and the patient had an immediate raging fever and erysipelas reaction. The tumour broke down, and only a small hard nodule was left. Zola enjoyed a further eight years of life before the tumour returned and caused his demise.

Coley went on to develop his own bacterial broth – a mixed bacterial vaccine (MBV) made from toxins of gram-negative Serratia marcescens. His first patient was a young German with an inoperable spindle cell sarcoma on the abdominal wall, attached to the pelvis and infiltrating the bladder. The intratumoural injections were followed by a temperature rise of 0.5° to 6° C, with tachycardia, chill, extreme trembling and severe headache. The tumour gradually regressed over a few months and finally disappeared. The patient recovered and lived another 26 years without recurrence, until suddenly dying in a subway station of myocarditis.

Coley showed the five-year survival rate for inoperable cancer increased from 28% to 64%, depending on the temperature of the induced fever; the higher the temperature, the better the outcome. However, his treatment had one fundamental defect: the remedy was unpredictable, with each patient responding in a unique way. Gradually the concept of thermal therapy was supplanted by newer therapies such as radiation and chemotherapy.

After Coley’s death in 1936, his daughter, Helen Coley-Nauts – founder of the Cancer Research Institute in New York – documented all the patients he and his colleagues had treated with MBV and tried to keep track of them. In 1953, she published her first detailed analysis, which attracted worldwide attention. In total, of 1200 cases treated with MBV, she found that more than 270 patients with inoperable cancer achieved complete remission.

In the 19th century, other methods of increasing body temperature included wrapping patients in plastic and dipping them in hot wax, placing them in hot rooms, or extracting their blood, heating it up then reinjecting it. Not surprisingly, success was varied and death was a common visitor. (Astonishingly, success was widely reported for STDs!)

Progress in local hypothermia therapy

Yet during this era, progress was being made in local thermotherapy. Frans Westermark developed a heated coil for cervical cancer with some success, but abandoned it because it caused patients excruciating pain. After Alessandro Volta invented his battery, electricity came into vogue for heating tissue. Joseph Recamier used electrical heat to remedy uterine cancer in 1830, while in 1874 Enrico Bottini invented his cauterio termogalvanico device for prostate cancer cauterisation. In 1889, John Byrne published his success in treating 367 uterine and cervical cancer patients using an electrical current to cauterise tissue, confirming that heat killed deeper-lying cancer cells while preserving normal tissue.

Following the work of physicists including James Clerk Maxwell and Heinrich Hertz on electromagnetism, many different alternating current devices were created – with Nikola Tesla getting on the act by demonstrating that high-frequency AC heated tissues, even using it to cure his pulmonary TB.

Jacque d’Arsonval’s experiments with high-frequency AC led to a treatment he called arsonvalisation. He developed a cage akin to a huge solenoid that surrounded the body, and tested it on himself by passing three amperes through his body with no ill effect except that he felt his body heating up. His arsonvalisation treatment cured many ailments, ranging from metabolic disease to haemorrhoids, and became very popular at the turn of the 20th century.

While Aronsval demonstrated how not to electrocute someone with AC current, he didn’t understand the heating effect, believing the heat produced was merely a side effect and that his treatment’s success was due to electromagnetic radiation. The heating effect was eventually explained by von Zeynek, a medical chemist who understood the heating of tissues was due to the body’s electrical resistance – just like an electrical heater with high-resistance wire works.

Then in 1907 Karl Nagelschmidt explained why arsonvalisation did not always work. Destruction of abnormal cells required the process of diathermy, which in Greek means “heating through”. Diathermy penetrated deeper into the body, whereas arsonvalisation could be superficial. The intensity of the diathermy determined if tissues would merely be heated or destroyed. Diathermy is achieved at greater currents and lower potential difference, whereas arsonvalisation depends on high tensions and lower currents by at least a factor of one. Because the body has a high resistance, the voltage drop-off is significant, preventing diathermy from occurring.

Between 1914 and 1927, William T Bovie discovered that high-frequency AC in the range 250,000–2,000,000Hz could be used to incise coagulated tissue and obtain haemostasis, and developed the first commercial electrosurgical device at Harvard University. Thus was born the diathermy so essential for today’s surgeons. It has remained the mainstay of thermally ablating localised cancerous lesions. It did not make its inventor wealthy – he sold his invention for $1. (The technique of heating tissues to cauterise them was actually discovered by an English surgeon called John Marshall, who presented it in a paper in 1886 after he became Chair of Surgery at University College Hospital. He didn’t commercialise his discovery.)

Thermal therapy using heat to kill tumours, rather than direct ablation using diathermy, reached its heyday with arsonvalisation

Thermal therapy using heat to kill tumours, rather than direct ablation using diathermy, reached its heyday with arsonvalisation. A decline in its popularity followed the discovery of ionising radiation by the great Wilhelm Röntgen. Röntgen had noticed a chemically coated plate started glowing when struck by radiation from a cathode tube that he was passing through glass. He called the radiation X-rays because he had no clue what they were.

After determining that a picture was developed on the plate by the radiation, he started to secretly experiment. When he held up a lead disc, he found that an image of his hand and the bones within appeared on the plate. Like a true gentleman, he cajoled his wife, Anna, to hold her hand in a beam for 15 minutes, and the world’s first medical X-ray plate was developed. Upon seeing the developed film she uttered the words, “I have seen my death.” It didn’t take long for these mysterious rays to be applied to cancer therapy, and for most of the 20th century, cancer care consisted of the triad of surgery, radiation therapy and, slightly later, chemotherapy. (As an afterword, Anna died at the advanced age of 80 years, not from radiation toxicity but from ‘nephritic cramps’.)

During this period there was strong scepticism of thermal therapy. In 1949 the German surgeon Bauer wrote that “these methods strongly impress patients but not their cancers”. However, work had started on seeing how thermal therapy would augment the effect of radiation therapy.

In 1927, Willis R Whitney of General Electric discovered that people standing close to shortwave transmitters experienced a 2-3°C rise in body temperature. This was known as irradiant radiofrequency heating, and it culminated in the development in 1931 of the Whitney Radiotherm, the world’s first true hyperthermia device. It was widely available in the 1930s and achieved remarkable results. By 1935, there were 100 papers published on hyperthermia, and in 1937 in Manhattan the first international conference on hyperthermia was held.

In the 1930s, a serious political battle occurred over the use of radiofrequency (RF) fields and their effect on tumours. On the one side were scientists convinced that the non-thermal effects of RF fields were responsible for tumour destruction, and on the other side were those in favour of the thermal effects. Even though both viewpoints held veracity, the thermal side gradually won the battle – possibly because of strong backing from the Rockefeller organisation – and by the late ’30s thermal therapy was considered a treatment modality on its own. However, it was to remain a fringe science until the post-war era sparked a serious revival of interest in thermal therapy.

On the technical front, the microwave in the gigahertz range had been discovered and it found application in many areas, including the ubiquitous microwave oven. Of course, proponents of thermotherapy turned their eyes to microwaves as a novel form of energy for heating the body. In the 1970s, the Swedish oncologist Jens Overgaard carried out 204 clinical studies on 10,000 patients showing the effectiveness of microwave technology in treating tumours, and whole-body hyperthermia and regional perfusion hyperthermic technologies became well established.

42°C – the toxic dose of hyperthermia therapy

However, the limitations of whole-body hyperthermia became glaringly obvious in view of the 42°C limit – the toxic dose of thermotherapy was established by George Crile as 42°C. In 1962 he discovered that heating some types of tumours in mice for an extended period to between 42–50°C would selectively destroy the cancer cells but not healthy ones. Crile explored inducement of thermal tolerance by tumours implanted in the feet of experimental mice and the rate of thermal damage as the temperature was increased (after his experiments, many mice were left hobbling around on one foot). He also found that thermotherapy combined with radiotherapy increased damage to both cancerous and healthy tissues, making the treatment dubious.

In the mid-1960s in socialist East Germany, Manfred von Ardenne – a brilliant physicist and prolific researcher running his own institute, free from commercial pressure and with vast family funds at his disposal, with 600 patents to his name – realised that heat on its own was largely ineffective without causing significant injury to normal cells. He also stumbled on the non-comparability of in vitro and in vivo studies. His work moved into the realm of thermosensibilisers – the forerunner of thermotherapy use with chemotherapeutic drugs.

Von Ardenne also found that hyperglycaemia with tissue acidification was a potent tumouricidal weapon (in an acidic environment, erythrocytes lose their pliability and block vessels, leading to tumour necrosis) and considered it more important than the heating effect. Furthermore, he discovered that acidification from thermotherapy also affects healthy tissue, so he introduced hyperoxygenation into the mix to protect normal tissue. His work was published in 1972 as selective multiphase cancer therapy (sCMT) and was gobbled up by Western science.

By the 1980s, the International Journal of Hyperthermia had been launched (and remains the most important journal on the subject), manufacturers of hyperthermic equipment had become established and whole-body hyperthermia had been superseded by localised applications

In the 1970s, US scientists drove the research, quantifying the time intervals of thermotherapy at different temperatures before tumour cell death occurred. Precision instruments for determining temperatures in tumours were developed, along with chemotherapeutic drugs and techniques for perfusion hyperthermia. By the 1980s, the International Journal of Hyperthermia had been launched (and remains the most important journal on the subject), manufacturers of hyperthermic equipment had become established and whole-body hyperthermia had been superseded by localised applications.

In the 1990s and early part of the 21st century, however, large-scale trials of hyperthermia showed little benefit, forcing the whole industry to undergo a reset – a topic too vast to cover in this brief history. The renaissance started in the second decade of the 21st century, with concepts like intravesical hyperthermic chemotherapy [such as Combat Medical’s HIVEC®], in which the use of heated chemotherapy drugs in intravesical bladder-cancer therapy has started to flourish, and the era of nanomedicine and hyperthermia is also being established.

Abridged from The History of Thermal Therapy Part 1, originally published in Urology, Uro-Oncology and Sexology Update (Winter Edition / Issue 1, 2022)

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