TRATAMIENTO TERCIARIO

2.1 HISTORY O F HYPERTHERMIA

The concept o f using heat to destroy malignant tissue dates to antiquity. Its therapeutic value was first recognised in ancient Egypt with the earliest reference carbon dated to 1700 B.C. An account is given o f breast tumours fulgurated using the glow ing tip o f a firedrill (Breasted J H., 1930). The ancient Romans and Greeks used heat extensively as a therapeutic tool; its combination o f haemostatic and ablative properties were considered particularly valuable (Milne., 1907).

The beneficial effects o f heat were also recognized by Hippocrates (370-470 B.C) stating that "those diseases which medicines do not cure, the knife cures; those which the knife cannot cure, cautery cures; and those which cautery cannot cure are reckoned to be wholly incurable". Hippocrates used heat to destroy a growth on the neck o f a patient and described in detail many febrile illness and the benefits o f the associated fever. In Hindu folklore, the therapeutic benefits o f heat were propagated by the Hindu god Susrata who deemed "caustic is better than knife and cautery is better than both."

The impetus to use hyperthermia, that is, induction and maintenance o f elevated body temperatures to treat cancer is based on reports o f spontaneous tumour remission in patients who suffered episodes of high fever. In a review paper o f this topic (Selawry et al., 1957), 150 cases o f spontaneous remission associated with the onset o f acute febrile illness were encountered out o f 450 histologically proven tumours. In the latter half o f the 19th century, several reports appeared on the deliberate induction o f fever inducing maladies in an attempt to treat malignant disease (Busch., 1866; Fehleisen., 1883). The most prominent cam e from Coley (1893, 1894, 1911). In a summary o f this work, 65 cases o f histologically proven but inoperable recurrent sarcomas were treated by interstitial tumour injection o f a mixed toxin o f Streptococcus Pyogenes and Bacillus Prodigiosus. Ten patients survived 3 to 5 years, 17 survived 5 to 10 years, 7 survived 10 to 15 years and a further 7 survived 15 to 18 years giving a 5 year survival rate o f 48% (31/65). All treatments seem ed to be well tolerated. Spurred on by Coley's results, several workers used "Coley's toxin" to treat a wide spectrum o f malignancies with various degrees o f

success. This field was reviewed by Coley's daughter and son (Coley-Nauts et al., 1946). It was noted that at least 15 different toxins o f varying potency were used at varying time intervals using different administration routes to a mixture o f connective tissue and epithelial tumours considered inoperable at the time o f inoculation. O f 312 cases, 192 displayed tumour regression in one form or another with a 77% 5 year survival. O f the 5 year survivors, 15 later died o f recurrent disease. The prerequisites for a good therapeutic response were a systemic temperature o f 39 to 40°C sustained for several 24 to 48 hour periods. Possible mechanisms o f action o f Coley's toxins include a direct action o f the bacterial toxins on the tumour or induction o f an immunological anti-tumour response in addition to any thermally mediated cytotoxic response. Despite the anecdotal nature o f this work, its therapeutic implications cannot be denied.

In 1931, a significant step was made in understanding the relationship between temperature and its duration o f application to induce cell death. Ficus and Fisher (1931) demonstrated with each degree temperature rise in centigrade above 44°C , the time necessary to achieve cell death is halved. Thus for the first time, a rough dosimetric quantification could be made when treating patients.

W anen (1935) treated 32 patients with hopeless widespread métastasés arising from a range o f primary sites considered beyond the scope o f available treatments o f the day. Patients were heated in an insulated cabinet initially by diathermy current by direct attachment. The temperature was maintained by radiative heating within the cabinet using high powered lamps. One patient died during treatment but 52% (16/31) showed marked to moderate improvement as judged by extent of tumour shrinkage and speed of emergence of recurrent disease. Median survival from treatment was 8.5 months.

Despite these encouraging results which should have fuelled further research and development in the application o f hyperthermia for human cancers, a period o f decline followed aided in no small part by the advent o f Roentgen's x-rays and the dawn o f the era o f radiotherapy. However, the failure of radiotherapy as a panacea for all cancers allowed a resurgence o f interest in hyperthermia from a scientific and clinical point o f view. This commenced in the late 1950's blossoming from the mid 60's onwards.

2.2

TECHNIQUES FOR IN D U C IN G HYPERTHERMIA

The definition o f "conventional" hyperthermia is based on raising and maintaining tissue temperatures in the range o f 4 2 .5 -4 5 °C . The ideal technique for inducing hyperthermia should

1. Be minimally or non-invasive. 2. Simple to use.

3. Generate reproducible energy outputs which should be easy to control.

4. Produce precise and accurate energy deposition in superficial and deep organs allowing unifomi temperatures to be achieved in the heated volume.

5. U tilise reliable equipment which should be efficient, cost effective and o f acceptable dimensions.

Despite frequent technical developm ents, no single system as yet fulfils all these criteria. Heterogeneous tumour histology, tumour volume and anatomical locations make it unrealistic to expect any one system to be satisfactory for all common tumours encountered in clinical practice.

Techniques for inducing hyperthermia are divided in two broad categories - whole body hyperthermia and localized/regional hyperthermia, each enjoying the support o f its proponents. The various techniques available and the rationale for their application will now be discussed.

2.2.7 WHOLE B O D Y HYPERTHERMIA

Coley (1893) injected bacterial toxins into patients with cancer to induce a systemic fever in the hope o f producing tumour remission. This constitutes the first description o f w hole body hyperthermia (WBH) for tumour therapy. The aim o f conventional WBH techniques is to raise and maintain core body temperature to 41.5-42°C . The relative thermal sensitivity o f organs such as the liver and heart impose a constraint on temperatures that can be safely achieved. Human malignant disease is in most cases a systemic illness. Unlike regional techniques which confine the therapeutic assault on a relatively small

volume o f overt disease, W BH is a biologically more attractive treatment concept in attempting to treat overt and occult disease.

A ll techniques increase core body temperature by reducing patient heat losses combined with an input o f thermal energy into the patient. This can be achieved in one o f three ways: