Locoregional Hyperthermia
Universität Bochum, Grönemeyer-Institut in co-operation ASIAN NATURAL ENERGY CO., LTD.
Prof. Dr. med. E. Dieter Hager, Prof. Dr. med. habil. D. Grönemeyer, Prof. Dr. med. H. Sahinbas
Dr. med. J. Baier, PD Prof. Dr. rer. nat. et. med. M. W. Trogisch,
Key words hyperthermia, cancer therapy locoregional hyperthermia, deep hyperthermia, superficial hyperthermia, endocavitary hyperthermia, interstitial hyperthermia, RF capacitive heating, laserinduced thermotherapy, highfrequer induced thermotherapy, radiation therapy, chemotherapy, clinical trials
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Introduction
Hyperthermia is one of the promising new multidisciplinary approaches to cancer therapy. The rationale for raising temperature in tumour tissue is based on a direct cellkilling effect at temperatures above 4142 'C and a synergistic interaction between heat and radiation as well as various antineoplastic agents. The thermal doseresponse depends also on microenvironmental factors such as pH, and P02 in the tumour tissue. Depending on the physical characteristics of the energy field applied, also other mechanisms of tumour destruction or growth retardation may be relevant. Tissuespecific 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 the surrounding 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 [15], the cytoskeleton, the iongradient and membrane potential [611], synthesis of macromolecules and DNAreplication [1214], intra and extracellular pH (acidosis) [1517] and decrease in intracellufar ATP [17]. Genes can be upregulated or downregulated by heat, for example the heatshock 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 heatshock 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))
- Partbody 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.
With RF capacitive heating devices delivering 827 MHz and annular phasedarray systems delivering 60430 MHz electromagnetic waves local and regional deep hyperthermia (DHT) can be applied for superficial and [arger deep seated tumours. As a generel 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 tumours and higher frequencies for more superficial tumours. Molecules with dipoles, like water, are vibrating in such alternating electromagnetic fields which will be measured as heat.
With capacitivelycoupled electrodes and perfusion of 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 partbody hypertherrnia (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 tumour. For interstitial hyperthermia high frequency needle electrodes at 375 kHz (f.e., high frequencyinduced thermotherapy; HiTT), microwave antennas, ultrasound transducers, laser fibre optic conductors (laserinduced thermotherapy; UTT), or ferromagnetic rods, seeds or fluids (magnetic fluid hyperthermia (f.e. with nanoparticles), MFH) are implanted into the tumour. In most 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 tumour thermonecrosis at a distance of 1 to 2 cm around the hot source. This technique is suitable for 15 tumours less than 5 cm in diameter.
Insertion of antennas or electrodes into lumens of the human body such as the oesophagus, rectum, urethra, vagina and the uterine cervix are used for endocavitary hyperthermia. With this technique larger applicators than for interstitial hyperthermia with larger 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 TNFa (see chapter #). Extracorporal heat exchange is commonly used to heat up blood for the perfusion of extremities.
Fig. 1. Technical devices for deep hyperthermia: a) high frequency induced thermotherapy, b) RF capacitivelycoupled electrodes, c) multiantenna applicator (12 dipole pairs)
Deep hyperthermia (DHT) is referred to the induction of heat in deep seated tumours eg, of the pelvis abdomen, liver, lung, or brain by external energy applicators. The technical features for the treatment of deep seated tumours are interstitial applicators (f.e. conductive), electromagnetic antennadipole arrangements, capacitivecoupled electrodes, ultrasound, and magnetic fields (see table 1). The technique used, will restrict the application to certain body areas.
Table 1. Different heat dellvery rnethods
Heat delivery methods / ExamplesConductive / Cavitational water-heating; extra-corporal
blood heating; RF needles
Radiative / Infrared light (IR-A, -B, -C)
Mechanical / Ultrasound
Antennas / Multi-antenna-dipole applicators
Capacitive / Condenser
Inductive / Ferromagnetic rods/seeds/fluids
Bioactive / Pyrogens, cytokines
The different electromagnetic techniques used for transferring energy in regional deep hyperthermia are:
- radiofrequencies (RFDHT) between 827 MHz
- high frequencies (HFDHT) between 60430 MHz (decimetre waves) and
- microwaves (MWDHT) at frequencies larger than or equal 1 GIlz (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 tumour 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 nonthermal 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 827 MHz.
First experimental and clinical experiments have been performed in the 1960s with radiofrequencies in the range between 8 and 27 MHz (LeVeen). This technique is most frequently used in Japan and Russia. In Japan most clinical research has been performed with RFtechnique 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 (BSD2000) 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 hypertherrnia
1. Superficial hyperthermia
Superficial tumours can be heated by (a) waveguide applicator, (b) spiral applicator (c) current sheet applicator, (d) ultrasonic applicator, (e) RFneedles and (f) infrared sources. Electromagnetic applicators for superficial hyperthermia have a typical frequency of 150430 MHz. Most convenient for local hyperthermia are waterfiltered infrared sources. The therapeutic depths with these applicators is about 3 cm.
By Medline database research up to October 2003, six randomised prospective phase 111 trials (RCT) on radiotherapy alone compared with radiotherapy combined with hyperthermia could be identified (Tabie 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: Randornised controlled trials on superficial hyperthermia
Tumoursite / Experi- / Control / No. / Primary / HT / Survival / Refmental / Of / endpoints / better / Benefit
Pts
Head & neck / RT + sHT / RT / 65 / Response / Yes / No / 39
(primary) / at 8 weeks
Melanoma (metastatic or / RT + sHT / RT / 68 / Complete / Yes / No / 40
recurrent) / response
Superficial (head&neck, / RT + sHT / RT / 245 / Initial / possibly / No / 41
breast, miscellaneous / response
Head and neck / RT + sHT / RT / 44 / Response / Yes / Yes / 42
(N3 primary) / (2-6 times)
Breast (advanced / RT + sHT / RT / 307 / Initial / Yes / No / 43
primary or recurrent / response
Head & neck, breast, / RT + 2x / RT+ / 173 / Response / No / No / 44
sarcoma melanoma / sHT / lxsHT
Abbreviations: RT: radiotherapy; sHT: superficial hyperthermia
2. Interstitial hypertherrnia
For direct thermal ablation of tumours by interstitial hyperthermia most frequently ferromagnetic rods or seeds are implanted into the tumour and excited by an alternating external magnetic field. For the treatment of glioblastoma this treatment modality has been shown to improve overall survival [45,46] (table 3).
Table 3. Randornised controlled trials with interstitial hyperthermi
Tumour site / Experimental / Control / No / Primary / HT / Survival / RefOf / endpolints / better / benefit
Pts
Head&neck, / iRF + iHT / iRT / 184 / Response / No / No / 45
breast,
melanoma, others
Glioblastoma / RT + iRT + iHT / RT + iRT / 79 / 2-year / Yes / Yes / 46
survival / - --
,Abbreviations: iRF: interstitial radiofrequency; RT: radiotherapy; iRT. interstitial radiotherapy;
iHT: interstitial hyperthermy
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 (UTT) or special HF needle electrodes (HiTT), is a new therapeutic modality for palliative and potentially curative therapy of primary liver tumours and liver metastases, especially if surgery is not acceptable or the tumours 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 laserinduced thermotherapy was applied for the first time by Hashimoto et al. [81] for the treatment of hepatic tumours and in the last years further developed by Vogel et al. [82]. In a nonrandomised 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 ÜTT a local tumour control rate of 97.3% after six months followup 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 tumour resection. First results of the RF needle technique are comparable with LiTT or tumour resection [84,85,86,87,88]. These methods for the nonsurgical treatment of tumour patients, preferably for inoperable malignant nodules of the liver (hepatocellular carcinoma and metastases) is highly promising. Also other tumours from the brain, breast, thyroid and parathyroid, lung and bone can be treated by this method.
The advantages of these methods are that they carl be applied. if surgery is not acceptable or the tumours are not resectable with low risk compared to surgery at different times repeatedly 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
- ultrasoundguided application and
- lower costs.
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].
3. Endocavitary hypertherrnia
Via intraluminal placed antennas heat can be applied in organs such as the oesophagus rectum, urethra (prostate), vagina, and the uterine cervix. Radiofrequencies, high frequencies and microwaves are most frequently used for the endocavitary hyperthermia (Table 5).
Table 5. Randornised controlled and observational trials with endocavitary hvperthermia
Tumor site / Experi- / Con- / No. / OR [%] / OR [%] / Survival / Remarks / Ref.mental / trol / of / Control / with HT / benefit
Pts-
Oesophagus / CT + HT / CT / 40 / 19 / 41 / No / RCT / 28
Oesophagus / RT + HT / 53 / 8 / 70 / RCT / 29
Oesophagus / RT + CT + / 53 / 8 / 27 / RCT / 30
HT
Oesophagus / RT + CT + / Rt+ / 66 / 59 / 81,2 / Yes / RCT / 47
HT / CT
Oesophagus / Ext. RT / ext. / 66 / Yes / OT / 32
MW + HT / RT
Rectum / RT + HT / RT / 115 / Yes / RCT / 48
Rectum / RT + CT + / RT+ / 36 / Yes / OT / 52
HT / CT
Bladder, / MW + CT / CT / 52 / CR: 22 / CR: 66 / Yes / RCT / 53
neoadj.
Bladder, adj. / MW + CT / CT / 58 / Rec: 64 / Rec: 15 / Yes / RCT / 54
Bladder, / hyperthermic / 10 / 90 / Yes / OT / 55
recurrent / perfusion +
CT
Abbreviations: RT: radiotherapy; CT: chemotherapy; MW: microwaves; RCT: randomised controlled
trial OT: openIabel observational study; CR: complete response; Rec: recurrence after adjuvant
treatment; neoadj.: neoadjuvant; adj.: adjuvant
4. Regional deep hyperthermia
4.1. Deep hyperthermia with multiantenna applicator systems
Tumours in the abdominal area can also be heated up by arrays of antennas, which are arranged as dipole antenna pairs in a ring around the patient. The Sigma60 applicator of the BSD2000 system is a widely used applicator, which consists of four dipole antenna pairs. The novel multiantenna applicator SigmaEye 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 tumour. Frequencies in the range of 100150 MHz are used for this technique.