The Ongoing History of Thermal Therapy for Cancer

Abstract

Through 5,000 years of practice, physicians, surgeons, clergy, or lay people have utilized thermal therapy to treat mass lesions now known as cancer. The methods have changed dramatically over this time span and certainly the techniques have improved the efficacy and safety, but fundamentally, hyperthermic therapy is usually a local or regional treatment for most cancer patients. Fortunately, hyperthermia used in combination with chemotherapy or ionizing radiation continues to improve outcomes. We will briefly describe the historic role of hyperthermia in cancer care as well as modern expectations based on technological advancements. In particular, we will focus on the role of hyperthermia for cancers that do not have other, more effective treatments.

Background

Hyperthermia has been used with an “intent to cure ” tumors for at least 4,000 years, and as a tool for the destruction of tumor masses well before that.¹ Tumors refer to any growth or mass that has developed unexpectedly. Well before there was any understanding of the molecular basis for cancer, let alone the ability to diagnose cancer, there was an understanding that cutting or burning of these lesions was an appropriate therapy for some affected individuals. In fact, Hippocrates^{1, 2} describes that if a tumor “cannot be cut, it should burned. If it cannot be burned, then it is incurable.” Shockingly, for many cancers this is still the case.

While chemotherapy may “cure ” a few fortunate patients with various types of cancer, malignant diseases such as metastatic hepatocellular carcinoma (HCC) are usually incurable with no meaningful five-year survival probability in the majority of patients. In other patients who have locally advanced unresectable hepatic lesions, radiofrequency thermal ablation is a useful and potentially curative therapy for HCC. Notwithstanding the few patients who have some benefit from transhepatic arterial embolization, there is no curative systemic or regional cytotoxic chemotherapy for HCC. The most recently approved targeted therapy for HCC, sorafenib, increases median survival of patients with unresectable HCC by three months.³ Patients with unresectable metastatic lesions (such as colorectal cancer) to the liver that are amenable to RFA have a median overall survival of 25 to 30 months, in general. ⁴

There are multiple forms of hyperthermic therapy. The previously described RFA technique is a local therapy involving intratumoral placement of a needle electrode that can produce tissue temperatures as high as 100°C following activation of an electrical current. Alternating electrical current dissipation and ionic stimulation within tissue surrounding the electrode causes hyperthermia. Regional hyperthermia has been used in combination with regional chemotherapy during resection of extremity soft tissue sarcomas or as treatment for in transit limb metastases from melanoma.⁵ In these cases, the elevated tissue temperature is maintained for extended periods of time. This takes the form of an isolated limb perfusion of chemotherapy warmed to 42°C-45°C for 60 minutes or longer.⁵ Likewise, hyperthermic intraperitoneal chemotherapy is another regional hyperthermic treatment often performed simultaneously with resection of peritoneal malignant disease.⁶ Finally, whole body hyperthermic therapy has been utilized by inducing fevers with toxins⁷ or externally warming entire patients up to 42°C for extended periods of time.^{8, 9}

It is often quoted that Hippocrates “managed” superficial tumors with cautery or direct ablative therapy, but it is not clear if he was actually describing the treatment of cancer.¹ Interestingly, the side effects he mentions include weakness, neurological changes, hemorrhage, and death, which are all adverse events that are similar to what is seen today with whole body hyperthermic treatment.^{1, 9, 10} Around the Middle Ages and later, instruments were designed and shaped for direct application of heat to kill tumors or cauterize bleeding, albeit without the benefit of adequate regional or general anesthesia (Figure 1).

Figure 1.

Fourteen different instruments utilized for cautery as engraved by Jonas Arnold Deliveavit (ca. 1666). Image was acquired from The National Library of Medicine's Images from the History of Medicine collection in the public domain.

Finally, the goal of hyperthermic therapy is to capitalize on the difference in thermotolerance between normal and cancer cells.¹¹ Mammalian cells die when exposed to temperatures above 55°C for more than a few minutes, however, these normal cells tolerate temperature ranges from 41°C-43°C for hours. Importantly, each half of a degree increase in cellular temperature is associated with increased cell death. Cancer cells in general do not tolerate these temperatures nearly as well or as long. Finding the appropriate balance of temperature and duration is finding the balance between the desired cancer cell death and undesirable normal cell toxicity.

Early electrosurgery

Electrosurgical procedures in the first half twentieth century included destruction of cancerous tissues, enlarged lymph nodes, and cauterization of nodules left after enucleation of other masses.^{12, 13} Interestingly, these included intraabdominal procedures of the uterus and ovaries¹² as well as intrathoracic procedures for cancers and infections.¹³ In 1900, the first modern example of curative electrosurgery for cancer was documented when an artist who had a cutaneous carcinoma accidently touched an electrical wire. The current “treated” his cutaneous carcinoma via hyperthermia and the concept of electrofulguration was born.¹⁴ Soon thereafter, Dr. William T. Bovie and Dr. Harvey Cushing developed and clinically implemented an electrosurgical device for decreasing intraoperative blood loss.¹⁴ Hyperthermic electrothermal ablation can directly trace its history to this moment.

Development of modern techniques

Modern ablative techniques require direct contact between a probe, the target tumor, and surrounding normal tissue. Depending on the modality and intensity of treatment, there is an immediate zone of intratumoral necrosis, a zone of apoptosis, and a zone of hyperemia without frank cell death.¹⁵ Ideally, there will be a margin of normal tissue death in order to ensure the death of all cancer cells.⁴ Although there have been many extremely well done studies and reviews during the 1970's investigating the effects of hyperthermia on normal and cancer cells, a review article by Field and Bleehen described the current understanding of hyperthermia in the treatment of cancer that remains accurate to this day.¹⁶

Effective local or regional hyperthermic cancer therapy can be induced by either longer heating durations at temperatures of 41-45°C or by short duration treatment of cancer cells with higher temperatures (or both).¹⁷ Likewise, many, but not all, cancer cells respond differently than their normal cell origins to hyperthermic therapy.¹⁶ The difference between these two responses permits a general method to treat cancers with hyperthermia. This is not to suggest that all cancers can be treated in the same manner, but this approach has worked well in RF ablation of primary and secondary liver malignancies.¹⁸ The approach is to maximize the coagulative necrosis of the malignancy in situ while accepting limited necrosis or apoptosis of surrounding normal parenchyma. In this way, excess normal tissue is not needlessly injured while “oncologically” safe margins are maintained. Furthermore, all cancer cells are presumed to be within the area of coagulative necrosis and immediately killed during the procedure. The balance of treatment effectiveness, patient safety, and normal hepatocyte tolerance resulted in a nearly uniform practice of treating properly selected hepatic tumors for ~ 10 minutes with tissue temperatures of at least at 60°C - 65°C.⁴

More recent examples of direct electrosurgery are seen in the practice of endobronchial procedures and cervical lesions. ^19-21 While loop electrosurgical procedures are standard therapy for pre-malignant cervical lesions, endobronchial ablative therapy is not standard for cancers of the upper airways currently. However, they provide interesting and effective use of hyperthermic cautery based on the principles previously described. Interestingly, complete excision of pre-malignant or early malignant cervical lesions confers extremely high rates of cure for a disease, much like HCC, that otherwise carries a very poor prognosis when it is found to be advanced.^22-24

Modern ablative techniques

RF ablation of unresectable metastatic hepatic colorectal malignancies is the prototypical local tumor ablative procedure.²⁵ Likewise, RF ablation for primary hepatocellular carcinoma, neuroendocrine hepatic metastases, and other unresectable hepatic lesions is very common.²⁶ Often, RF ablation is performed synchronously with hepatic resection, the gold standard for surgical management of primary and secondary liver malignancies.^{25, 27} Finally, management of esophageal dysplastic lesions can often be safely managed with RF ablation.²⁸

Microwave ablation is slowly becoming more popular in the USA whereas it has been very useful in Europe and Asia for many years.²⁹ While monopolar RF ablation works by inducing an alternating electrical current from the probe to the tumor with excess energy dissipated through the patient to large grounding pads, microwave ablation works by exploiting rapid oscillation of water molecules based on the dipole moment of water around a microwave-emitting probe(s). The current in RF ablation passes via the path of least resistance, potentially resulting in asymmetric ablation patterns. Microwave ablation, however, will destroy anything within the confines of the field for a given treatment duration and power, including a potentially higher risk to damage normal tissues such as bile ducts and vascular structures.^{29, 30}

Cryoablation is the technique of using extremely cold probes to bring the temperatures of surrounding tumors to below the cytotoxic freezing threshold (less than approximately −20°C to as cold as −130°C) for up to 10 minutes with subsequent active heating for typically 2-3 cycles.^{31, 32} While systems vary, most utilize the conversion of high-pressure gas to cold low-pressure liquid to reach these extremely low temperatures. The urologic oncology community utilizes cryoablation more so than RF ablation to treat prostate cancer^{33, 34} while there is evidence that in hepatic lesions, RF ablation is more effective than cryoablation.^35-37

Future directions

While invasive RF ablation remains the standard of care in the USA, many surgeons expect that intratumoral probe microwave ablation will become a second standard therapy for unresectable cancers. Unfortunately, microwave ablation rapidly produces excessive heat that potentially destroys everything within its field, and as such, is not appropriate for use near vital, critical structures such as the biliary confluence or the ureter. However, as research investigates better ways to protect these important structures, the role of microwave ablation will certainly increase.

Two “futuristic” treatments are noninvasive nanoparticle-mediated intracellular hyperthermic cytotoxicity and irreversible electroporation (IRE). Gold and gold-based nanoparticles are in pre-clinical and early clinical development as a means to induce targeted hyperthermia.^38-40 Through the use of near-infrared lasers or nonionizing radiofrequency fields, multiple groups have demonstrated high specificity for killing targeted cancer cells in vitro and in vivo.^{39, 41-43} While there are some ongoing clinical trials investigating the use of nanoparticle-induced hyperthermia as a targeted cancer treatment, this therapy is still a few years away form being available for clinical trials.

IRE is the technique of placing electrodes on either side of lesion in situ and inducing an electric field between them.^{36, 44} Appropriately constructed electric fields will permanently create cell membrane defects (i.e., pores) that result in cell death without hyperthermic injury. Similar to microwave ablation, any cell within the electroporation volume will die, but acellular structures (extracellular components of bile ducts) should remain intact as there is not a potential across them. IRE devices are available in the USA, but studies are on-going.

Finally, high intensity focused ultrasound is 10 to 1000 times more intense than diagnostic ultrasound.^{45, 46} Targeted tissues (i.e., ultrasound probe is focused on a tumor) absorb high intensity acoustic energy which is converted to heat. Coagulative necrosis is typically achieved within a few seconds.³⁶ Early phase trials are on going for HCC, prostate, and other cancers.

Conclusion

The history of ablative therapies for cancers has been one of increasing the efficiency and specificity of treatment, not necessarily drastically changing the goals of the treatment per se. From the time of antiquity where a heated probe cauterized a skin lesion to today where an intratumoral needle electrode passes electricity to a liver lesion, the challenge has always remained to kill the cancer without harming the patient. New technologies should permit less invasive hyperthermic therapy while non-invasive hyperthermic therapy will be a reality in the near future. While today we treat cancers with invasive local or regional hyperthermia techniques, it is not unreasonable that in the future we will manage cancers with targeted noninvasive hyperthermia.