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Locoregional Hyperthermia


* Corresponding Author: BioMed-Klinik GmbH, Tischberger Str. 5-8, D-76887 Bad Bergzabern, Germany. Email: edh@biomed-klinik.de

Locoregional hyperthermia can be differentiated into external, interstitial and endocavitary hyperthermia. Different heat delivery systems are available: antennae array, capacitive coupled, and inductive devices. Depending on localization and size of the tumour different methods and techniques can be applied: superficial, intratumoral (thermoablation), deep hyperthermia, endocavitary, and part-body hyperthermia. Randomized clinical trials have been performed mostly with electromagnetic applicators for superficial hyperthermia in combination with radiotherapy, deep hyperthermia with and without radiation, and endocavitary hyperthermia in combination with chemotherapy and radiotherapy. In randomized clinical trials it could be demonstrated, that loco-regional deep hyperthermia with antennae array or capacitive coupled hyperthermia devices may increase response rate, disease free survival and overall survival of patients with cancer in combination with radiotherapy or chemotherapy without increasing the toxicity of standard therapies.


Hyperthermia is one of the most promising new multidisciplinary approaches to cancer therapy. The rationale for raising temperature in tumor tissue is based on a direct cell-killing effect at temperatures above 41-42°C and a synergistic interaction between heat and radiation as well as various antineoplastic agents. The thermal dose-response depends also on microenvironmental factors such as pH, and pO2 in the tumor tissue. Depending on the physical characteristics of the energy field applied, also other mechanisms of tumor destruction or growth retardation may be relevant. Tissue-specific electromagnetic interactions may be possible, depending on frequency and applicator technique used, due to inhomogeneities in the relative dielectric permittivity, relative magnetic permeability, specific conductivity, and ion distribution in cancer tissue compared to normal tissue.

The effects of hyperthermia on the host and cancer tissue are pleiotropic and depend mainly on the temperature and the physical techniques applied. The biological and molecular mechanisms of these effects are changes in the membrane,1-5 the cytoskeleton, the ion-gradient and membrane potential,6-11 synthesis of macromolecules and DNA-replication,12-14 intra- and extracellular pH (acidosis15-17) and decrease in intracellular ATP.17 Genes can be up-regulated or down-regulated by heat, for example the heat-shock proteins (HSP).18

Synergistic effects by interactions with antineoplastic agents, radiation and heat can be several powers of ten even at moderate temperatures. In addition, reduced chemotherapy resistancy, possibly due to increased tissue penetration, increased membrane permeability, and activated metabolism, has been observed.

Immunological effects of hyperthermia may play an additional role in cancer therapy such as immunological effects on cellular effector cells (emigration, migration and activation), induction of cytokines, chemokines and heat shock proteins (chaperones), and modulation of cell adhesion molecules. The induction of heat-shock proteins might increase specific immune responses to cancer cells.

Locoregional hyperthermia can be differentiated into

A. External hyperthermia

  • Local hyperthermia (short waves/radiofrequencies (SW/RF), microwaves (MW))
  • Regional deep hyperthermia (RF, MW, ultrasound (US))
  • Part-body hyperthermia (RF, MW, infrared (IR), heat perfusion)
B. Interstitial hyperthermia with
  • RF electrodes (f.e., needles)
  • HF or MW antennas
  • laser fibres
  • ultrasound transducers
  • magnetic rods/seeds and fluid
C. Endocavitary hyperthermia (sy.: intraluminal)
  • RF electrodes (f.e., coils)
  • radiative (IR, laser)
  • heat sources (hot fluid perfusion, extracorporal perfusion)
depending on the method of the external heating devices and the area treated with hyperthermia (Fig. 1).

Figure 1. Technical devices for deep hyperthermia: A) high frequency induced thermo-therapy; B) RF capacitively-coupled electrodes; C) multi-antenna applicator (dipole pairs).

Figure 1

Technical devices for deep hyperthermia: A) high frequency induced thermo-therapy; B) RF capacitively-coupled electrodes; C) multi-antenna applicator (dipole pairs).

With RF capacitive heating devices delivering 8-27 MHz and annular phased-array systems delivering 60-430 MHz electromagnetic waves local and regional deep hyperthermia (DHT) can be applied for superficial and deep seated tumors. As a general physical rule: the higher the frequency of the electromagnetic field the less deep the penetration depth will be. Therefore lower frequencies are used more frequently for deep seated tumors and higher frequencies for superficial tumors. Molecules with dipoles, like water, can be excited in such alternating electromagnetic fields which will be measured as heat.

With capacitively-coupled electrodes and perfusion with heated fluid larger anatomical areas like the peritoneum, the bladder, the pleural cavity and the whole liver and lung or extremities can be heated up, which is called part-body hyperthermia (PBHT). Depending on the frequencies applied and with new applicator techniques and with sufficient monitoring PBHT is also possible with dipole antennae devices.

Interstitial hyperthermia delivers the heat directly at the site of the tumor. For interstitial hyperthermia high frequency needle electrodes at 375 kHz (f.e., high frequency-induced thermotherapy; HiTT), microwave antennas, ultrasound transducers, laser fiber optic conductors (laser-induced thermotherapy; LiTT), or ferromagnetic rods, seeds or fluids (magnetic fluid hyperthermia (f.e. with nanoparticles), MFH) are injected or implanted into the tumor. In some cases the interstitial hyperthermia is combined with a brachytherapy by an afterloading method. With these applicators a heat can be applied high enough to induce in tumors thermonecrosis at a distance of 1 to 2 cm around the hot source. This technique is suitable for 1-5 tumors less than 5 cm in diameter.

Insertion of antennas or electrodes into lumens of the human body such as the oesophagus, rectum, bladder, urethra, vagina and the uterine cervix are used for endocavitary hyperthermia. With this technique larger applicators than for interstitial hyperthermia with higher penetration depth can be applied.

Perfusional hyperthermia with fluids (water, blood) is used to deliver heat with fluids into cavities like the peritoneum, the pleural space, or the bladder. The perfusate is combined with antineoplastic agents or cytokines, like TNF-α (see Chapter entitled “ Perfusional Peritoneal Hyperthermia”). Extracorporal heat exchange is commonly used to heat up blood for the perfusion of extremities.

Deep hyperthermia (DHT) is referred to the induction of heat in deep seated tumors-e.g., of the pelvis, abdomen, liver, lung, or brain-by external energy applicators. The technical features for the treatment of deep seated tumors are interstitial applicators (f.e. conductive), electromagnetic antenna-dipole arrangements, capacitive-coupled electrodes, ultrasound, and magnetic fields (see Table 1). The technique used, will restrict the application to certain body areas.

Table 1. Different heat delivery methods.

Table 1

Different heat delivery methods.

The different electromagnetic techniques used for transferring energy in regional deep hyperthermia are:

  • radiofrequencies (RF-DHT) between 5-27 MHz
  • high frequencies (HF-DHT) between 60-430 MHz (decimetre waves) and
  • microwaves (MW-DHT) at frequencies larger than or equal 1 GHz (centimetre waves).

The absorption of the electromagnetic field (EMF) is depending from physical properties of the penetrated tissue, like conductivity and dielectricity which may cause focusing effects and electromagnetic coupling. The distribution of the temperature within tumor tissue is inhomogeneous due to intra- and extratumoral perfusion regulations, electric characteristics of the tissues and thermal conductivity, and ranges between 39 and 43°C. In addition to the thermal effects, frequency dependent non-thermal effects may play an essential role. Physical aspects (impedance and interaction with dipoles) let expect a special role for EMF in the radiofrequency range between 1-30 MHz.

First experimental and clinical trials have been performed in the 1960s with radiofrequencies in the range between 8 and 27 MHz (LeVeen). This technique is now most frequently used in Japan and Russia. In Japan most clinical research has been performed with RF-technique at 8 MHz.49 In Europe, especially the Netherlands and Germany, most frequently high frequency technique systems with dipole antennae operating at frequencies of 60 to 120 MHz (BSD-2000) are used in clinical research. Since the end of the eighties 13.56 MHz RF capacitive heating devices are available also for superficial and deep hyperthermia in Europe, especially in Germany and Italy.

Clinical Trials on Hyperthermia

Superficial Hyperthermia

Superficial tumors can be heated by (a) waveguide applicator, (b) spiral applicator, (c) current sheet applicator, (d) ultrasonic applicator, (e) RF-needles and (f ) infrared sources. Electromagnetic applicators for superficial hyperthermia have a typical frequency of 150-430 MHz. Most convenient for local hyperthermia are water-filtered infrared sources. The therapeutic depths with these applicators is about 3 cm.

By Medline database research up to October 2003, six randomized prospective phase III trials (RCT) on radiotherapy alone compared with radiotherapy combined with hyperthermia could be identified (Table 2). In all of these trials the combination radiotherapy plus hyperthermia showed better response rates. Overall survival benefit was only noted in one RCT trial.

Table 2. Randomized controlled trials on superficial hyperthermia.

Table 2

Randomized controlled trials on superficial hyperthermia.

Interstitial Hyperthermia

For direct thermal ablation of tumors by interstitial hyperthermia most frequently ferromagnetic rods or seeds are implanted into the tumor and excited by an alternating external magnetic field. For the treatment of glioblastoma this treatment modality has been shown to improve overall survival45,46 (Table 3).

Table 3. Randomized controlled trials with interstitial hyperthermia.

Table 3

Randomized controlled trials with interstitial hyperthermia.

The percutaneous, minimal invasive interstitial thermal ablation by means of laser or high frequency current (radiofrequency or microwave fields) which are introduced through a fibre optic conductor (LiTT) or special HF needle electrodes (HiTT), is a new therapeutic modality for palliative and potentially curative therapy of primary liver tumors and liver metastases, especially if surgery is not acceptable or the tumors are not resectable. For RF thermo ablation multiple array needle electrodes (LeVeen needle) or hollow needle electrodes which can be perfused with physiological saline solution (Bechtold) are used. The needles are heated up with high frequency alternating current.

The laser-induced thermotherapy was applied for the first time by Hashimoto et al,81 for the treatment of hepatic tumors and in the last years further developed by Vogel et al.82 In a non-randomized trial Vogel et al, could show that in a total of 646 patients with 1.829 liver metastases up to 5 cm in diameter, mainly from colorectal (n = 1.126 metastases) and breast (n = 294 metastases) carcinoma by LiTT a local tumor control rate of 97.3% after six months follow-up could be achieved.83 The median survival rate of 39.8 months for colorectal liver metastases and 55.4 months for liver metastases of the breast are comparable with data from literature on surgical tumor resection. First results of the RF needle technique are comparable with LiTT or tumor resection.84-88 These methods for the non-surgical treatment of tumor patients, preferably for inoperable malignant nodules of the liver (hepatocellular carcinoma and metastases) is highly promising.

Also other tumors from the brain, breast, thyroid, parathyroid, lung and bone, and malignant lymphomas can be treated by this method.

The advantages of these methods are that they can be applied:

  • if surgery is not acceptable or the tumors are not respectable,
  • with low risk compared to surgery,
  • at different times repeatedly, and
  • on an outpatient basis and at lower costs.

The perfused needle electrodes have advantages compared to other techniques:

  • increased thermolesion up to 40 to 50 mm diameter compared to 10 to 15 mm by increased conductivity around the needle
  • single needle system instead of multi array antennae systems
  • thin needles with about 2 mm diameters
  • ultrasound-guided application and
  • lower costs for the needles.

In the future, magnetic fluid (f.e, ferromagnetic nanoparticles) will be added to the therapeutic arsenal, which can be heated up by an external alternating magnetic field (magnetic field hyperthermia, MFH).89 Very promising phase I/II studies have been closed.

Endocavitary Hyperthermia

Via intraluminal placed antennas heat can be applied in organs such as the oesophagus, rectum, urethra (prostate), vagina, and the uterine cervix. Radiofrequencies and microwaves are most frequently used for the endocavitary hyperthermia (Table 4). A survival benefit could be shown in most clinical studies.

Table 4. Randomized controlled and observational trials with endocavitary hyperthermia.

Table 4

Randomized controlled and observational trials with endocavitary hyperthermia.

Regional Deep Hyperthermia

Deep Hyperthermia with Multi-Antenna Applicator Systems

Tumours in the abdominal area can be heated up by arrays of antennas, which are arranged as dipole antenna pairs in a ring around the patient. The Sigma-60 applicator of the BSD-2000 system is a widely used applicator, which consists of four dipole antenna pairs. The novel multi-antenna applicator Sigma-Eye consists of 12 dipole pairs. Each antenna pair can be controlled in phase, amplitude, frequency and electric field to focus the heat in the area of the tumor. Frequencies in the range of 60-150 MHz are used for this technique.

Two randomized phase III trials with multi-antenna applicators have been published up to the end of 2003 and two trials are ongoing (Table 5). In two of these trials external radiotherapy was compared with combined radiotherapy and regional deep hyperthermia in the treatment of patients with primary cervix uteri (stage III) and primary or recurrent pelvic tumors. The number of complete response rates could be improved in both clinical studies and a survival benefit was demonstrated in one trial.

Table 5. Randomized trials on regional deep hyperthermia with antenna applicator systems.

Table 5

Randomized trials on regional deep hyperthermia with antenna applicator systems.

Regional Deep Hyperthermia with Radiofrequency Capacitive-Coupled Electrodes

Deep seated tumors can be heated by RF capacitive-coupled electrodes. For these systems mostly radiofrequencies in the range between 8 and 27 MHz are used. In the 1960s Le Veen developed a machine for induction of hyperthermia in tissue with radiofrequencies by capacitively-coupling of electromagnetic fields (EMF) at 13.56 MHz. It has been shown that RF capacitive heating devices can effectively raise the temperature of lung and liver tumors in humans (see for review ref. 49), though van Rhoon failed to raise the temperature with capacitive plate applicators at 13.56 MHz in tumors of the pelvic area of patients above 40.9°C.56 This technique can even be applied for the treatment of brain tumors38

RF Hyperthermia without Combination with Radio- or Chemotherapy

Clinical trials with hyperthermia mostly have been performed in combination with radiation or antineoplastic agents (Tables 6, 7). But some first results from hyperthermia trials with capacitive coupled radiowaves with 13.56 MHz in the treatment of patients with primary tumors or metastases in the liver, lung, pancreas and brain without combination with radio- or chemotherapy are promising and should be validated with randomized trials.

Table 6. Randomized trials with RF capacitive coupled heating devices.

Table 6

Randomized trials with RF capacitive coupled heating devices.

Table 7. Non-randomized clinical trials with RF capacitive coupled heating devices.

Table 7

Non-randomized clinical trials with RF capacitive coupled heating devices.

Lung Cancer

In a prospective open-label observational study 63 patients with histological proven small cell lung cancer (n = 10) and non-small cell lung cancer (n = 53) at far advanced stage of disease have been treated with regional deep hyperthermia (DHT) with RF capacitive coupled short waves of 13.56 MHz.36 All patients were inoperable, refractory or at stage of relapse after prior surgery (30%), chemotherapy (46%), and/or radiotherapy (46%). 86% of the patients presented with restrictive disorder of pulmonary ventilation. The median time between first diagnosis of inoperabel cancer or relapse (local and distant progression) and beginning of DHT was 3.9 months. Only 2 patients were treated with palliative chemotherapy 8.4 and 28.5 months after the start of DHT due to tumor-associated symptoms (e.g., pain).

The median overall survival time (MST) of all patients was 14.0 months from 1st diagnosis of advanced lung cancer. From relapse after surgery or 1st diagnosis of inoperable stage of disease the MST was 10.3 months. The 1- and 2-year survival rates from progression of disease were 37% and 18%, respectively.

Liver Metastases from Colorectal Cancer

Patients at advanced stage of colorectal cancer with liver metastases have been treated with deep hyperthermia alone or in combination with chemotherapy (5-FU + FA). RF capacitive coupled electrodes with a radiofrequency of 13.56 MHz (RF-DHT) was applied.37

Median total survival time of all 80 patients from 1st diagnosis of disease was 34.4 months, and from 1st diagnosis of progression (metastases or relapse) 24.5 months, and from beginning of first RF-DHT alone (n = 50) 16 months. Patients who received RF-DHT followed by chemotherapy in combination with hyperthermia (n = 30) survived at a median of 11 months. Survival rates of all patients (n = 80) from first diagnosis of progression (metastases or relapse) were 91 ± 3 %, 51 ± 6% and 31 ± 6 % at 1, 2 and 3 years, respectively.

Pancreas Cancer

In a retrospective analysis of the treatment of 20 patients with inoperable or relapsed cancer of the pancreas the treatment with RF-DHT (13.56 MHz) resulted in a median survival time of 12 months.68

In a prospective open trial with 46 patients with far advanced (non-resectable, relapsed or metastatized) pancreatic carcinoma were treated with RF capacitive heating at 13.56 MHz.69 Median age at study entry was 62 years (range 38-82), median Karnofsky's index 50% (range 30-90). Six patients suffered from jaundice and 10 showed ascites at study entry. The multimodal non-toxic treatment consisted of regional RF-deep hyperthermia (13.56 MHz, Synchrotherm, Italy) combined with complementary therapies (prteolytic enzymes, antihormonal therapy, etc.).

The median overall survival of the patients was 10.5 months (range 2-76, mean 18 months) from first diagnosis of disease and 5 months from the beginning of the multimodal treatment. Most patients experienced essential improvement in quality of life (68% freedom from pain, 24% marked pain relief); 64% improved appetite (thereof 24% normal appetite) over a relatively long period of time, and reduction of jaundice and ascites.


The primary aim of this study was to define the feasibility of RF-DHT deep hyperthermia (RF-DHT) in the treatment of patients with progressive gliomas after standard therapy and to estimate the effect on survival.38 Between 09/97 and 09/02, 36 patients with gliomas (9 patients with anaplastic astrocytome WHO grade III, and 27 patients with glioblastoma multiforme WHO grade IV were treated with RF-DHT and Boswellia caterii, an inhibitor of leukotriene synthesis for inhibition of peritoneal edema. DHT was performed with a 13.56 MHz capacitive coupled RF-device. Patients with inoperable or subtotally resected and recurrent gliomas (WHO grade III and IV) with progression after radio- and/or chemotherapy and a Karnofsky Performance Score of ≥ 50% were included. The study was designed as a prospective open-label, single-arm, mono-centred observational phase II trial. Primary endpoints were median survival time and survival-rate (Kaplan-Meier estimation). The survival was calculated on the basis of an intention-to-treat-analysis.

Deep hyperthermia of brain tumors with RF capacitive hyperthermia at 13.56 MHz is feasible and without severe side effects. The RF-DHT-treatment is well tolerated and even patients at far advanced stages of disease can be treated. Complete and partial remission or retardation of tumor growth could be observed (Fig. 2). Prolongation of MST compared to historical controls and improvement of quality of live (EORTC QLQ-C30 questionnaires) is clinically significant. The median overall survival time of patients with anaplastic astrocytoma (WHO grade III) was 106±47 months [95% conficence intervall 14 to 197 months] and for patients with glioblastoma multiforme (WHO grade IV) 20±5 months [95% confidence interval 10 to 31 months]. The survival rates are listed in Tables 8 and 9.

Figure 2. Complete remission from anaplastic astrocytoma (WHO grade III) with RF-DHT at 13.

Figure 2

Complete remission from anaplastic astrocytoma (WHO grade III) with RF-DHT at 13.56 MHz lasting more than 3+ years after recurrence following surgery, radiotherapy and chemotherapy.

Table 8. Survival probability: anaplastic astrocytoma WHO grade III (n=9).

Table 8

Survival probability: anaplastic astrocytoma WHO grade III (n=9).

Table 9. Survival probability: glioblastoma multiforme WHO grade IV (n=27).

Table 9

Survival probability: glioblastoma multiforme WHO grade IV (n=27).

Non-Thermal Effects

The differences in the relative dielectric permittivity and magnetic permeability, the electric conductivity and the different ion distribution between normal and malignant tissue may explain different physical and physiological behaviour of the cells in an electric or magnetic field. It is possible that especially electromagnetic fields in the range between 1 and 30 MHz exhibit non-thermal antineoplastic effects on cancer cells by direct electromagnetic coupling, f.e. with the cell membrane, receptors or ion channels. Tumour growth inhibition has been shown also for interactions with alternating magnetic fields.71

The application of low power electric fields (<5W) has also found to be effective against cells and tumors without increasing the temperature.72-75 Yet few studies discuss the biological mechanisms involved in the mechanisms involved with the interactions between EMF and tissue. In his book, Exploring Biological Closed Electric Circuits (BCEC) Nordenström from the Karolinska Institute in Stockholm79 describes different circulatory system pathways for which any serious disruption in the flow of energy and material can produce error, malfunctions, disruptions and disease. O'Clock from Minnesota State University could demonstrate a proliferation suppression of malignant cells (retinoblastoma cells) by direct electrical current within a 10 to 15 μA range.80

Non-equilibrium thermal effects might be-at least partially-responsible for antineoplastic effects in tumor tissue. Capacitively-coupled energy transfer in the frequency range between 8 and 27 MHz may not penetrate the cell membrane and will be absorbed primarily in the extracellular space. A constant energy delivery may maintain over time a temperature gradient between the extra- and intracellular space, causing ionic currents through the membrane which depolarizes and therefore destabilizes the membrane.76,77 An increased transmembraneous water influx by the thermal flux can increase the intracellular pressure, which is about 30% above the normal.76 Since malignant cells typically have relatively more rigid membranes than normal cells due to increased phospholipid concentrations,78 an increase in pressure will selectively destroy more malignant cells.

These effects might be the reasons why RF capacitively coupled hyperthermia may be used for the treatment of areas which have been contra indicated for other methods of hyperthermia, such as of the liver, lung, pancreas and brain.


Locoregional hyperthermia may contribute to therapeutic improvements in the treatment of cancer patients. Randomised controlled phase III trials have shown that these methods increase at least at several indications the response rate, disease free and overall survival of patients with cancer without increasing the toxicity of other combinational treatments. Nevertheless, the different methods are associated with systemic and local side-effects. For three types of tumors, the locally advanced cervical cancer, advanced head and neck tumors and glioblastoma, a survival benefit has been shown in randomized controlled trials. In other tumors, such as local recurrent breast cancer and recurrent melanoma an increase in local response but no positive effect on recurrence-free or overall survival has been demonstrated. The recurrence rate of carcinoma of the bladder can be reduced markedly by hyperthermic perfusion. Patients with peritoneal metastases from ovarian cancer respond much better to hyperthermic perfusion chemotherapy compared to systematic chemotherapy, especially after first line therapy.

The superficial, interstitial and perfusional hyperthermic methods provide at the time the most effective hyperthermic methods with significant improvements in clinical outcome in oncology, as quality of life and overall survival.

Further technical improvements are desired to optimize the therapeutic outcome. The optimal technique, i.e., applied frequency, maximal temperature, time of exposure, time interval with other antineoplastic modalities, has still to be defined. Non-invasive techniques for the measurement of the intratumoral temperature distribution may overcome the present burdened and risky invasive measurements.

Non-thermal effects may also play a role by direct interactions of electromagnetic and ultrasonic waves in cancer tissue, on subcellular and molecular levels. There are some interesting hints, showing that deep hyperthermia with radiofrequencies may have some different effects and may exhibit antineoplastic activity without radio- or chemotherapy. Marked improvements in quality of life, pain relief and prolongation of survival could be observed in first observational studies. These encouraging results deserve to be confirmed in randomized clinical trials.

But, with respect to evidence-based gradings of clinical trials it should be mentioned that K. Benson et al,50 and J. Concato et al,51 could show in meta-analysis from 235 clinical studies that well-designed observational studies do not systematically overestimate the magnitude of the effects of treatment as compared with those in randomized, controlled trials on the same topic.


I thank Mrs. M. Riese for the literature search and manuscript assistance.


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