HYPERTHERMIA IN CANCER TREATMENT

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HYPERTHERMIA IN CANCER TREATMENT
03/02/2008
ajaypalsingh
Pharmainfo.net

THE USE OF HEAT IN THERAPY
The application of heat in the treatment of disease was first recorded in the ancient civilizations of Egypt, Greece, and Rome from as early as 2000 BC [1].
Fever is one of the body's own defensive and healing forces, created and sustained for the deliberate purpose of restoring health. The high temperature speeds up metabolism, inhibits the growth of the invading virus or bacteria, and literally burns the enemy with heat. Fever is an effective protective and healing measure not only against colds and simple infections, but against such serious diseases as polio and cancer. In biological clinics, overheating therapies or artificially in the treatment of acute infectious diseases, arthritis and rheumatic disease, skin disorders, insomnia, muscular pain and cancer.
The treatment of malignance by hyperthermia was first mentioned by Celsus who observed that the early stages of tumour formation were ''particularly suitable'' for this form of therapy. Hippocrates noted that ''illness not cured by heat its incurable''. The enthusiasm for heat application became diminished after 1537, when Pare demonstrated that treatment by cautery produced ''unacceptable consequences'' of inflammation [2]. In 1866, Busch raised the concept of cancer eradication in humans by the use of systemic hyperthermia, following the reported disappearance of a sarcoma of the face following about of erysipelas.
Coley in 1893 also observed the regression of cancer in ten patients who developed pyrexia due to erysipelas. He subsequently injected bacterial toxins directly into tumour with variable results. Wagner-Jauregg received the Nobel Prize in medicine for work involving the therapeutic application of hyperthermia. Following observation that people with malaria had a lower incidence of syphilis, he subsequently induced malaria in people suffering from syphilis and obtained a 30% remission [3]. The first account of the use of regional hyperthermia was reported in 1943 by King, where he also observed evidence of hepatic damage. Wallace et al. used total body hyperthermia to treat resistant gonococcal infections. In 1909, Schmide suggested the use of hyperthermia as a potentiating effect to radiotherapy in patients with malignancy[4]. Further evidence has subsequently evolved of the synergistic effects of hyperthermia and radiotherapy. Advances since the1970s have focused on total body hyperthermia, regional perfusion techniques and localized hyperthermia, by using energy source such as laser, microwave and ultrasound technology.
WHAT IS HYPERTHERMIA
Hyperthermia is a therapeutic procedure used to raise the temperature of tumor-loaded tissue to 40-43ºC. It is administered together with other cancer treatment modalities (multimodal oncological strategies).

BIOLOGICAL CHANGES FOLLOWING HYPERTHERMIA
The use of hyperthermia in the treatment of malignancy depends on the differential between tumor and normal cells to the application of this energy source. Temperature variations in tumors as well as 2ºC, maintained for 30 min may alter the fraction of tumor cells killed by a factor of more thane 100. Temperature applied in the range between 41 and 42ºC were lethal to tumor cells, whilst not damaging normal cells. In fact, the different therapeutic effect of hyperthermia between malignant and normal tissue may very well primarily depend on the vascular characteristic of the tumour. The deffering characteristics of the blood supply amongst various types of tumors may also explain the differential response of hyperthermia between different types of malignancies. In general, tumors have a relatively low blood flow and decreased vascular density when compared to normal tissue. The tumor vessels are characterized by large dilated, tortuous vascular lakes lined by a monolayer of endothelial cells. Abnormal branching patterns involving true loops, spirals, bifurcation and trifurcation and arteriovenous malformation indicate an inefficient circulation network. These abnormal characteristics are maximum at the center of the tumour. Minimal tumour vascular changes are seen at the periphery, where transition with the normal circulation of the host occurs. Sluggish blood flow has been confirmed by laser Doppler studies, which also shows that blood flow is minimal at the center of the tumour. The flow at the periphery of the tumour approaches the normal flow of the host. As the tumour increases in size, the tumor vessel diameter increases. In addition, autoregulatory mechanisms of the normal circulation and vessel response to hormonal and neural control is absent in the tumour vessel. When normal tissue is blood flow due to the inflammatory response, with resultant dissipation of heat and minimal tissue damage. This increase in blood flow may be heterogeneous and its degree often unpredictable.
The abnormal structure and sluggish circulation of the tumour vessels combined with a lack of autoregulation of flow makes tumour tissue more susceptible to heat application.
Controversy exists as to the actual response of tumour blood flow to hyperthermia, which may be variable under certain circumstances. Tumour blood flow either dramatically decreases or ceases following hyperthermia. The majority of experimental evidence indicate that this decrease in blood flow occurs immediately following application of heat. Other experiments suggest a minimal response of tumour flow to heat, but no subsequent compensatory increase, as seen in normal tissue [5]. Ultrastructural studies have indicated vascular endothelial destruction and luminal occlusion, prior to any cellular changes of the tumour. Initial damage to the capillary endothelial cells and blood flow occlusion may thus be a major cause of heat induced tumour cell death. Alternative experimental evidence indicate that tumour blood flow remains constant during hyperthermia, but decreases following cessation of heat for up to 4-6 h post treatment. A part from complete cell death, the viability of the remaining live cells deceases after heat treatment, increasing their susceptibility to other treatment modalities such as radiotherapy and chemotherapy. The cytocidal effects of heat may continue and even augmented following cessation of therapy. This may be related to continued exposure to hypoxia, acidosis, reduced ATP levels and inhibition of important cellular repair processes, Cells are most sensitive to hyperthermic treatment during the S phase, when DNA is being synthesised . In heat-treated cells, newly formed DNA fragments appear to be joined incorrectly and contain aberrant chromatids. Cell death subsequently occurs in these cells following mitosis. A part from the formation of defective DNA, hyperthermia may also cause synthesis to be completely inhibited through effects on replicon inhibition. Repair mechanisms are also affected by hyperthermia leading to mutagenic effects. Nucleoli, the site of rRNA synthesis are also preferentially destroyed by heat, together with other enzyme involved in RNA synthesis.
In general, during hyperthermia tumour vessels do not dilate, blood flow is diminished causing a great period of heat retention and thus an ability to sustain higher temperatures and increased tissue necrosis.
METHODS TO INCREASE THE TEMPERATURE
In the clinical setting, hyperthermia may be applied as whole body hyperthermia, interstitial hyperthermia or in association with regional perfusion techniques
Whole-body hyperthermia
Whole body hyperthermia was initially induced by submerging the patient in hot wax, plastic wrapping or the use of a perfusion suit. Extracorporeal systemic hyperthermia is now the method of choice in achieving whole body hyperthermia.
It allows a more homogeneous method of heating and is able to provide a higher sustained and constant temperature. The patients core temperature can be raised to tumoricidal levels with 20-30 min. Other methods presently being evaluated have included the use of hot water in a countercurrent distributor combined with a humidification system.
Using molten wax to raise the temperature to 41.8ºC, Pettigrew reported a response rate of 55% in 82 patients with advanced malignancy [6]. Larkin reported a significant response rate in 21 out of 24 patients with advanced malignancy by used total-body hyperthermia with external heating[7]. In 1979, Parks reported favorable effects of hyperthermia in a varied group of patient including advanced bronchogenic carcinoma and Kaposi's sarcoma[8].
Used in conjunction with chemotherapy, hyperthermia has synergistic effects whole –body hyperthermia has been combined with chemotherapy in advanced small cell carcinoma of the lung, but has been associated with considerable morbidity. In 19 patients with refractory sarcoma and malignant teratoma treated with total body hyperthermia to 41.8ºC and using ifosmide and carboplatin, there were seven partial remissions and eight cases of disease stabilization using a total of 49 thermo-chemotherapy treatment sessions[9].
Regional perfusion
Regional perfusion hyperthermia has been predominantly used clinically in patients with unrespectable recurrent sarcoma and melanoma of the extremities. There have also been reported cases of isolated pelvic perfusion in unrespectable carcinoma of the rectum, and for peritoneal carcinomatosis. The procedure was first performed by klopp in 1950. Hyperthermia limb perfusion to temperature of 41.5ºC was used in conjunction with melphalan in 85 patients with various types of malignancy. There was a complete response in 40% and a partial response in 42% of patient. Major complications occurred in 20% patients. isolated hyperthermia limb perfusion for the treatment of melanoma of the extremity has now been used for over 40 years, in conjunction with dose intensive delivery of anticancer agents such as melphalan, interferon gamma and tumor necrosis factor. At present, there is a lack of agreement of it is specific role and possible benefits.
Continuous hyperthermia peritoneal perfusion has been reported in ten patients with peritoneal carcinomatosis from colon and gastric cancer, using the chemotherapeutic regime of COPP. Three patients had resolution of their ascites, with five patients surviving beyond 12 month [10]. Isolated liver perfusion for liver metastases using extracorporeal circulating and vena cava occlusion has also been described.
Interstitial therapy
Interstitial therapy involves the delivery of heat specifically to the tumor tissue. There are two described techniques. The first involves the use of radiant heat devices or intracavity microwave for superficial advanced tumors, in combination with chemo or radiotherapy.
It has been applied in situations of advanced ulcerative breast cancer, chest wall recurrence, cervical lymphadenopathy and head and neck cancers. Using dual modality therapy (hyperthermia and radiotherapy) complete or partial remission rates between 30 and 100% have been reported[12]. A part from accessibility, prognostic factors include the depth and size of the lesion, as well as the histological characteristic of the tumor.
The second method of delivery is the use of laser fibres, ultrasound or microwave techniques to achieve focal high temperature for tumor of the liver, breast and pancreas. Significant tumor necrosis has achieved using these method.

Figure 1-1. Applicator types for induction of hyperthermia.

SUMMARY OF BENEFITS
Hyperthermia can be used by itself, and results in impressive shrinkage and even complete eradication (10-15%) of tumors. However, these results usually don’t last, and the tumors regrow. (In some animal experiments, cures were affected by hyperthermia. For example, in an animal experiment on transplanted mammary carcinoma, radiation alone produced no cures, heat alone produced 22% cures, and combined modality produced 77% cures). The synergistic effects of hyperthermia combined with radiation have been studied the most. Hyperthermia has been used for the treatment of resistant tumors of many kinds, with very good results. Combined hyperthermia and radiation has been reported to yield higher complete and durable responses than radiation alone in superficial tumors. In deep seated tumors, the effect of combined treatment is still under research. It is unfortunate that patients usually come to hyperthermia when other modalities have been exhausted. But even in these circumstances, hyperthermia allows re-radiating tissue that has already received the maximum dose. Rates of response in these patients are generally high. Hyperthermia is one way to overcome the radio resistance of tumor cells. It is possible to combine hyperthermia safely with further low dose radiation in situation where a radical dose has already been delivered. In addition, there seems to be evidence that whole body hyperthermia provides a measure of protection against radiation-induced thrombocytopenia. (And experiments in mice have shown an increase in platelet count 8 days after the administration of hyperthermia. The current theory states that whole body hyperthermia induces platelet stimulating hormonal factors. Hyperthermia improves the therapeutic index of TBI (total body irradiation), not only by increased neoplastic cell kill, but also by inhibiting the expression of radiation induced damage to the normal cell population. When it comes to chemotherapy, there are indications that some chemotherapeutic agents can be potentiated by hyperthermia. This can, in some agents, increase toxicities and the incidence of damage associated with them at the usual doses, or it can be taken advantage of in the sense of getting the same results with lower doses of the drug. In combination with chemotherapy, the type of drug, dose, temperature and time of administration all play a role. Vinca alkaloids and methotrexate exhibit only some additive cytotoxicity. Doxorubicin and dactinomycin are potentiated if heat follows, but inhibited if heat precedes them. Synergistic, supra-additive effects between heat and drug have been observed in bleomycin, cisplatin, cyclophosphamide, melphalan, mitoxantrone, mitomycin C, thiotepa, misonidazole, and 5-thi-D-glucose. Some agents not cytotoxic at normal temperature show cell killing abilities at higher temperatures: alcohols, amphotericin B, cysteine, and cysteamine. Drugs showing no enhancement are the antimetabolites (mixed results with 5FU and methotrexate) and taxanes. The increased effect seen by combining cytotoxic agents with hyperthermia is complex, but may be due to altered drug pharmakinetics such as increased solubility (e.g. nitrosureas and alkylating agents), altered plasma protein binding (e.g. cisplatinum) and activation of enzymatic processes (e.g. anthracyclines). The new agents interferon, TNF and lonidamine and some hypoxic cell sensitizers are all potentates by heat." Hyperthermia can augment the cytotoxicity without increasing myelosuppression, and reverse drug resistance to chemotherapeutic agents . It has recently been recognized that hyperthermia may also provide additional advantages in regard to drug delivery, particularly when the drugs of their carriers are relatively large. It has been shown in several studies that the use of hyperthermia can enhance the delivery of monoclonal antibodies to tumors with resultant improvement in anti tumor effects. The spread into tissues of liposome-carried chemo drugs increases considerably compared to that under normal temperature." And interesting information has emerged from hyperthermia studies that may become valuable in the future -- a certain heat shock protein seems to be expressed on the surface of malignant cells after hyperthermia, and is absent in normal cells. This creates the possibility that monoclonal antibodies can be designed to home in just on the malignant cells. Hyperthermia is also an immune system enhancer, and very effective in providing pain relief, controlling bleeding, and useful in other conditions such as prostatic hypertrophy and psoriasis.
SUMMARY OF RISKS
Hyperthermia side effects for the external methods include pain, unpleasant sensations and burns in a small percentage of patients. In the case of the internal pyrogens, which are sometimes bacterial toxins, the situation is more complicated, as bacterial toxins can induce serious, even fatal reactions in humans, depending on dosage. (I have not seen a study evaluating pyrogens’ side effects at safe doses.) Ultrasound hyperthermia in areas where the tumor is over a bone will cause bone pain. Whole body hyperthermia can result in neuropathies. Extracorporeal systemic hyperthermia is another mode, where the blood is routed from the body as in dialysis, for example, and is heated before returning to the body. It has two advantages higher possible temperatures, and more homogeneous heating. The side effects, however, have been considerable frequent persistent peripheral neuropathies, abnormal (and sometimes lethal) blood coagulation, some damage to liver and kidneys, and brain hemorrhaging and seizures. Hyperthermia should be administered to patients who are awake and can report any problems as they experience them. Analgesics can be administered if a patient has difficulty lying still for the duration of the session. Patient’s vital signs must be monitored frequently during the session. Cardiovascular disease and sometimes pace makers (dep. on the heat delivery method) are a contraindication for the treatment.

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