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Extreme Whole-Body Hyperthermia with Water-Filtered Infrared-A Radiation

* and .

* Correponding Author: A. von Ardenne—Von Ardenne Institute, Zeppelinstr. 7, D-01324 Dresden, Germany. Email: ceo@ardenne.de

The testing of various methods to realise extreme whole-body hyperthermia (eWBH) finally led to the utilisation of radiative systems. Among these the application of water-filtered infrared-A radiation (wIRA) distinguished itself by its high penetration, all the way into the capillary bed of the skin. With wIRA the interfering infrared-B and the infrared-C is eliminated from the heat radiation. Thus a clearly higher radiation power can be applied at a tolerable level than by applying unfiltered heat radiation. In two independent phase I clinical studies the high tolerance of eWBH (approx. 42°C/60 min) was proven in the scope of the so-called systemic cancer multistep therapy (sCMT) while applying wIRA. First proof of the retardation of tumour progression could be carried out by a retrospective observation study of over 490 sCMT treatment courses of cancer patients with various different tumour entities at an advanced stage. A phase I/II clinical study on the treatment of 19 patients with metastatic colorectal cancer with sCMT and wIRA in combination with chemotherapy suggests that sCMT may enhance the effect of chemotherapy. In a prior study on the treatment of patients with metastasized adenocarcinomas, only 3/19 patients remained in progression.

Introduction

Lamps with water-filtered infrared radiation for therapeutic applications had already been produced at the beginning of the 20th century.1

In 1931 A. Bachem2 could already prove that skin only featured a high transmission depth or penetration for heat radiation from the spectral region of infrared-A (760 nm … 1,400 nm). In the spectral regions of infrared-B (1,400 nm … 3,000 nm) and the close infrared-C (3,000 nm. 1 mm) on the other hand, the transmission is very slight which leads, at an application of a high radiation power, to an overburdening of the skin (fig. 1).

Figure 1. Transmission of electromagnetic waves in the spectral region of infrared-A, -B and -C through a human skin layer of a thickness of 1.

Figure 1

Transmission of electromagnetic waves in the spectral region of infrared-A, -B and -C through a human skin layer of a thickness of 1.4 mm.

As standard electric light bulbs and halogen lamps radiate approx. half of their energy in the spectral region of infrared-B and -C, this share of radiation has to be eliminated. This is possible with a water layer, which placed in the ray path, acts like an edge filter and eliminates the infrared-B and -C share from the heat radiation (fig. 2).

Figure 2. Transmission of electromagnetic waves in the spectral region of infrared-A, -B and -C through a water layer of defined thickness.

Figure 2

Transmission of electromagnetic waves in the spectral region of infrared-A, -B and -C through a water layer of defined thickness.

If a water layer of appropriate thickness is placed, for example, in front of a halogen lamp with approx. 2600°K filament temperature, this results in the spectral radiation distribution displayed in Figure 3. In this way heat radiation is generated with a spectral distribution, the focus of which is in the area of highest transmission of the skin. This is defined as water-filtered infrared-A radiation (wIRA).

Figure 3. Radiation spectrum of a halogen lamp after passing a water filter (water-filtered infrared-A radiation).

Figure 3

Radiation spectrum of a halogen lamp after passing a water filter (water-filtered infrared-A radiation).

U. Henschke3 provided an early quantitative substantiation for the tolerance of water-filtered infrared-A radiation. He publicised that for long-term application the maximum toleration of radiation intensity for water-filtered heat radiation was double as high as for standard bulb radiation. Unfortunately this knowledge did not lead to a wider range of application in the following decades in clinics.

For patients with advanced and metastasised malignant tumours, only a systemic therapeutic approach is adequate. Such a prerequisite is, among others, offered by the extreme whole-body hyperthermia (eWBH) with target temperatures around 42°C, which is usually combined with adapted chemotherapy today.4

After ten years of research and development in the field of radio frequency hyperthermia at 27 MHz to bring about a noncontact whole-body hyperthermia in combination with an increase of temperature locally5 (fig. 4), M. von Ardenne 1985 recognised the limits of the application at that time: The development of hot spots, impossibility of temperature mapping, high demand made on technology and shielding.

Figure 4. Radio frequency hyperthermia with a 27 MHz-SELECTOTHERM system for the noncontact combined whole-body and local hyperthermia with an applicator that can be focussed on the tumour (1987).

Figure 4

Radio frequency hyperthermia with a 27 MHz-SELECTOTHERM system for the noncontact combined whole-body and local hyperthermia with an applicator that can be focussed on the tumour (1987).

A way out of this dilemma was offered by the idea of thermal treatment of the outer body shell. As even according to the law of thermo-dynamics, it is only a question of time until the innermost point of an entity that is surrounded by an isothermal outer body shell is at the same temperature level as the outside body shell itself. To achieve this, a thermal source is required, the radiation of which only penetrates the millimetre area of the skin and is then almost completely absorbed. If this is successful, simple two-step temperature monitoring is possible by which the temperature of the skin (outside body shell) and, on the other hand, the body core temperature, is observed during hyperthermia treatment by inserting a temperature sensor into a body opening, e.g., the rectum.

Technical Realisation of Water-Filtered Infrared-A Radiation

Inspired by E. Braun, in 1985 M. von Ardenne once again took up the principle of water-filtered infrared-A radiation whereby he was able to implement the idea of heating up the body shell. The water-filtered infrared-A radiation penetrates into the capillary bed of the corium, where the direct transmission of heat into the blood circulation system takes place (fig. 5) and thus an equalisation of the temperature takes place in the whole organism.

Figure 5. Absorption of the infrared-A radiation in the various skin and tissue layers by superficial radiation (acc.

Figure 5

Absorption of the infrared-A radiation in the various skin and tissue layers by superficial radiation (acc. to Borchert and Jubitz) below: Intensity distribution of water-filtered infrared-A radiation

A system for extreme whole-body hyperthermia with water-filtered infrared-A radiation was developed in several generations in close collaboration with the photo dermatology department of the University Clinic Charité, Berlin.7 Such a system of the third generation is depicted in Figure 6. The patient lies on a knot-free net and is heated from top and from bottom by five radiator groups with water-filtered infrared-A radiation. The distribution of radiation intensity at patient level is adjusted manually, the temperatures are displayed and recorded without interruption.

Figure 6. Whole-body hyperthermia system for extreme whole-body hyperthermia with water-filtered infrared-A radiation of the type IRATHERM 2000 (Producer: Von Ardenne Institut für Angewandte Medizinische Forschung GmbH Germany).

Figure 6

Whole-body hyperthermia system for extreme whole-body hyperthermia with water-filtered infrared-A radiation of the type IRATHERM 2000 (Producer: Von Ardenne Institut für Angewandte Medizinische Forschung GmbH Germany).

An efficient system with water-filtered infrared-A radiation for whole-body hyperthermia was at disposal for the first time with this hyperthermia system. It is characterised by its open equipment design, good possibilities to observe the patient and good controllability of body temperature with the help of four temperature sensors. Despite the open equipment design a quick increase in temperature is possible. Independent of the developer, this medical technology was tested under clinical conditions and its suitability for whole-body hyperthermia was confirmed.8 Figure 7 shows a temperaturetime chart with the course of body core temperature (rectum/rekt) and three temperatures close to the surface (axilla/axil, hypogastrium/ubm, lumbar spine/lws).

Figure 7. Temperature-time chart with the course of 4 body temperatures (Therapy No.

Figure 7

Temperature-time chart with the course of 4 body temperatures (Therapy No. 880, Clinic for systemic Cancer Multistep Therapy Dresden, Germany).

Tolerance of Extreme Whole-Body Hyperthermia with Water-Filtered Infrared-A Radiation

The extreme whole-body hyperthermia is generally carried out in the form of systemic cancer multistep therapy (sCMT).9 The sCMT developed by M. von Ardenne consists of the three main steps, extreme whole-body hyperthermia, induced hyperglycaemia and relative hyperoxaemia which are usually combined with a chemotherapy protocol adapted to the respective tumour entity.10 In the meantime it has become general consensus that an extreme whole-body hyperthermia already has to be concomitant as supportive measure for the effective supply of the healthy tissue at an increased metabolic rate with a high blood sugar level and an increased oxygen rate.

The “good systemic tolerability” of extreme whole-body hyperthermia in the form of sCMT with water-filtered infrared-A radiation with only “minimal side effects” had already been proven for the first time in 1994 on 103 patients in the scope of a phase I clinical study.11 The cancer patients with metastasised and/or recurrent primary tumours received conventional pretreatment and were in a stage of progression. During the hyperthermia phase the patients were sedated by modified neuroleptic analgesia in a state of spontaneous respiration. This result was confirmed 5 years later by a phase I/II clinical study of another workgroup which sedated the patients by intubated anaesthesia (total intravenous anaesthesia).12 It confirmed that sCMT does not lead to any serious or sustained organ dysfunction and can therefore be regarded as a “safe therapy”.

The side effects displayed in Table 1 represent a therapy period of approximately 15 months which had been preceded by approximately 600 therapies with extreme whole-body hyperthermia.13 In this respect a routine can be accepted in the therapy method. All the cancer patients had metastatic cancer and were in a reduced general condition before treatment began.

Table 1. Side effects in 112 sCMT therapies of cancer patients in the stage of conventionally uncontrollable progression from 09/1995 to 12/1996 (figures = number of therapies).

Table 1

Side effects in 112 sCMT therapies of cancer patients in the stage of conventionally uncontrollable progression from 09/1995 to 12/1996 (figures = number of therapies).

First Clinical Results

So far only few clinical studies on the therapy of cancer patients with extreme whole-body hyperthermia using water-filtered infrared-A radiation have been publicised. Most of the cancer patients were in an advanced stage where there was a progression that was no longer controllable by the conventional methods of oncology.

In the scope of a retrospective observation study all the sCMTs carried out in a clinic in the period 12/1990 to 12/1995 were evaluated acc. to UICC criteria usually in combination with adapted chemotherapies (ChT).14 490 sCMT-one time therapies of random cancer patients (ø years) with different tumour entities were evaluated. The average body core temperature in the 60 min plateau was 41. 9 ± 0.3°C, the maximum blood sugar concentration in the temperature plateau was 27.0 ± 3.7 mmol/l. Figure 8 displays tumour entities evaluated depending on UICC criteria of which at least 15 patients received therapy. In a considerable share of patients the progression of the disease (PD) could be brought to a temporary standstill (NC) or even turned into a response (MR, PR, CR). The statistics of findings was made in a continued observation period of at least three months by two restagings at intervals of at least 4 weeks.

Figure 8. Individual evaluations related to diagnosis acc.

Figure 8

Individual evaluations related to diagnosis acc. to UICC criteria in tumour entities with ≥ 15 patients; 5% confidence interval for nonPD-PD limit.

Furthermore, in the scope of a prospective phase I/II study at the University Clinic Virchow, Berlin, patients with metastatic colorectal cancer were treated with sCMT in combination with ChT.15 The extreme whole-body hyperthermia was also implemented applying water-filtered infrared-A radiation at 41.8°C body core temperature for 60 min. Furthermore, an induced hyperglycaemia of approx. 22 mmol/l and a relative hyperoxaemia by the inhalation of an air mixture enriched by 50% oxygen was set. 8/19 patients responded to three therapy courses ChT (folinic acid + 5-FU + mitomycin C) (PR) and obtained three further courses of ChT alone (control group). 10/19 patients who had not responded to ChT (NC, PD) received three additional courses of ChT combined with sCMT (test group). One patient who did not respond to initial ChT (NC) declined sCMT therapy. The result of the therapy showed that a PR was induced in 3/10 patients and in a further 6/10 patients a PD could be prevented. Furthermore, despite the negative selection of the patients in the test group, a fairly similar course of progression-free survival was observed in the test and control group (fig. 9).

Figure 9. Progression-free survival in test and control group.

Figure 9

Progression-free survival in test and control group. Note: The graph does not represent a comparison of similar patient groups: all patients treated with sCMT plus ChT previously had not responded to three courses of conventional ChT. All patients treated (more...)

In the scope of a pilot study 19 patients with metastasised adenocarcinomas (breast n = 7, ovarian n = 5, colorectal n = 7) received therapy with the above- mentioned procedure of sCMT in combination with various ChT.16 All patients were refractory to standard ChT and with progressive disease. As a result of the therapy 9/19 patients showed a PR, 7/19 an NC. 3/19 patients showed further tumour progression.

The treatment of 2/2 patients with refractory germ cell tumours by the above mentioned procedure of sCMT combined with ChT (ifosfamide, carboplatin, etoposide) displayed a PR in both cases after three courses.17 This result and further observations of the course taken were encouragement enough to carry out a phase II study, which has not been concluded yet.

With extreme whole-body hyperthermia, but without making use of water-filtered infrared radiation, seven phase II studies and four phase III studies are being carried out in Germany (2004) apart from the named clinical studies.18

Even though this contribution primarily deals with whole-body hyperthermia, it should not remain unmentioned that the water-filtered infrared-A radiation is also suitable for the implementation of moderate hyperthermia or fever range hyperthermia. In this case the patients are treated with a “temperature dose” of 39°C/3 h up to 40°C/6 h. Currently research groups around J. Bull,19,20 and W. Kraybill21 are working in this field with unfiltered heat radiation, whereby the patients are heated in a chamber. The water-filtered infrared-A radiation in an open equipment design, on the other hand, allows for the one-sided heating of the patient - fever range hyperthermia. Nevertheless, a quick increase in temperature at good tolerance and controllability is given of the temperature level aimed at. The temperature/pulse—time chart with a fever range hyperthermia above the aimed at temperature displayed in Figure 10, shows the good controllability of the hyperthermia with water-filtered infrared-A radiation. Furthermore, the heat radiation concentrated on the patient can be individually adjusted to spot and intensity.

Figure 10. Temperature/pulse - time chart of a therapy with water-filtered infrared-A radiation between fever range hyperthermia and extreme whole-body hyperthermia.

Figure 10

Temperature/pulse - time chart of a therapy with water-filtered infrared-A radiation between fever range hyperthermia and extreme whole-body hyperthermia. Hyperthermia equipment IRATHERM 1000 (Therapy No. 2, Clinic Eubios Grünhain, Germany).

Conclusions

The tolerance of the water-filtered infrared-A radiation to realise a whole-body hyperthermia in the form of sCMT in clinical routine could be proven by phase I studies. Initial clinical results allow for the assumption that this method could intensify the effect of ChT, as could be displayed in the example of patients with metastatic colorectal cancer and adenocarcinomas refractory germ cell tumours with small case numbers. The still unsatisfactory situation of available data for the proof of effectiveness and first positive results are an encouragement to carry out higher-grade studies. It is still absolutely unanswered as to which extent this method could decrease the chance of formation of metastases if, for instance, implemented post-operatively.

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