Download Locoregional Hyperthermia

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,
laser-induced thermotherapy, highfrequer induced thermotherapy, radiation therapy, chemotherapy,
clinical trials
Correspondence address:
ASIAN NATURAL ENERGY CO., LTD.
968 T. Y. Court B 1 Thonglor
Sukhumvit 55, 10110 Bangkok - Thailand
Fon: +66 (0) 2 714 9238
Fax: +66 (0) 2 392 6767
[email protected], www.asnaer.com
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 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 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.
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 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 [1-5], the cytoskeleton, the ion-gradient and membrane potential
[6-11], synthesis of macromolecules and DNA-replication [12-14], intra- and extra-cellular pH
(acidosis) [15-17] and decrease in intracellufar ATP [17]. Genes can be up-regulated or downregulated
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 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))
- 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.
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 [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.
2
With capacitively-coupled 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 part-body 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 frequency-induced
thermotherapy; HiTT), microwave antennas, ultrasound transducers, laser fibre optic conductors
(laser-induced 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 1-5 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 TNF-a (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 thermo-therapy, b)
RF capacitively-coupled electrodes, c) multi-antenna 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
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 dellvery rnethods
Heat delivery methods
Conductive
Radiative
Mechanical
Antennas
Capacitive
Inductive
Bioactive
Examples
Cavitational water-heating; extra-corporal
blood heating; RF needles
Infrared light (IR-A, -B, -C)
Ultrasound
Multi-antenna-dipole applicators
Condenser
Ferromagnetic rods/seeds/fluids
Pyrogens, cytokines
The different electromagnetic techniques used for transferring energy in regional deep hyperthermia
are:
- radiofrequencies (RF-DHT) between 8-27 MHz
- high frequencies (HF-DHT) between 60-430 MHz (decimetre waves) and
- microwaves (MW-DHT) at frequencies larger than or equal 1 GI-lz (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
3
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 8-27 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 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 hypertherrnia
1. Superficial hyperthermia
Superficial tumours 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 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
Experimental
Control
Head & neck
(primary)
Melanoma (metastatic or
recurrent)
Superficial (head&neck,
breast, miscellaneous
Head and neck
(N3 primary)
Breast (advanced
primary or recurrent
Head & neck, breast,
sarcoma melanoma
RT + sHT
RT
No.
Of
Pts
65
RT + sHT
RT
68
RT + sHT
RT
245
RT + sHT
(2-6 times)
RT + sHT
RT
44
RT
307
RT + 2x
sHT
RT+
lxsHT
173
Primary
endpoints
HT
better
Survival
Benefit
Ref
Response
at 8 weeks
Complete
response
Initial
response
Response
Yes
No
39
Yes
No
40
possibly
No
41
Yes
Yes
42
Initial
response
Response
Yes
No
43
No
No
44
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).
4
Table 3. Randornised controlled trials with interstitial hyperthermi
Primary
endpolints
HT
better
Survival
benefit
Ref
iRT
No
Of
Pts
184
Response
No
No
45
RT + iRT
79
2-year
survival
Yes
Yes
46
- --
Tumour site
Experimental
Control
Head&neck,
breast,
melanoma, others
Glioblastoma
iRF + iHT
RT + iRT + iHT
,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 laser-induced 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
non-randomised 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 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 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 non-surgical 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
- ultrasound-guided 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).
5
Table 5. Randornised controlled and observational trials with endocavitary hvperthermia
Tumor site
Oesophagus
Oesophagus
Oesophagus
Oesophagus
Oesophagus
Rectum
Rectum
Bladder,
neoadj.
Bladder, adj.
Bladder,
recurrent
Experi-
Con-
No.
OR [%]
mental
trol
of
Control
CT + HT
RT + HT
RT + CT +
HT
RT + CT +
HT
Ext. RT
MW + HT
RT + HT
RT + CT +
HT
MW + CT
CT
Pts40
53
53
19
8
8
Rt+
CT
ext.
RT
RT
RT+
CT
CT
66
59
52
CR: 22
MW + CT
hyperthermic
perfusion +
CT
CT
58
10
Rec: 64
Remarks
Ref.
41 No
70
27
RCT
RCT
RCT
28
29
30
81,2 Yes
RCT
47
OR
[%]
with
HT
Survival
benefit
66
Yes
OT
32
115
36
Yes
Yes
RCT
OT
48
52
CR: 66
Yes
RCT
53
Rec: 15
90
Yes
Yes
RCT
OT
54
55
Abbreviations: RT: radiotherapy; CT: chemotherapy; MW: microwaves; RCT: randomised controlled
trial- OT: open-Iabel observational study; CR: complete response; Rec: recurrence after adjuvant
treatment; neoadj.: neoadjuvant; adj.: adjuvant
4. Regional deep hyperthermia
4.1. Deep hyperthermia with multi-antenna 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 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 tumour. Frequencies in the
range of 100-150 MHz are used for this technique.
Two randomised phase 111 trials with multi-antenna applicators have been published up to the end of
2003 and two trials are ongoing (table 6). 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 111) and Primary or recurrent pelvic tumours. The number of complete response
rates could be improved in both clinical studies and a survival benefit was demonstrated in one trial.
6
Table 6. Randomised trials on regional deep hyperthermia with antenna applicator systems
Tumour sit
Experimental
Con
trol
Cervix uteri
(primary, stage 111)
Primary or recurrent pelvic
(cervix, rectum, bladder)
Rectum (uT3/4)
RT +
DHT
RT +
DHT
RT + CT
+ DHT
CT +
DHT
Soft-tissue sarcoma
(high risk)
Primary
endpoints
HT
better
Survival
benefit
Ref
RT
No.
of
Pts
40
CR
Yes
No
18
RT
361
CR, Survival
Yes
Yes
19
RT +
CT
CT
>150
Disease-free
survival
Disease-free
survival
>150
ongo
-ing
ongo
-ing
4.2. Regional deep hyperthermia with radiofrequency capacitive-coupled electrodes
Deep seated tumours 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 tumours in humans [see for review 491 and can also
be appliedfor the treatment of brain tumours [38], though van Rhoon failed to raise the temperature
with capacitive plate applicators at 13.56 MHz in tumours of the pelvic area of patients above 40.9'C
[56].
Table 7. Randornised trials with RF capacitive coupled heating devices
Tumor site
Cervix
Cervix
Cervix
Cervix
Colorectal
Gastric
Colorectal
Bladder
Experimental
RT + HT
RT + HT
RT + HT
RT + HT
RT + HT
RT + HT
RT + HT
RT + HT
Control
RT
RT
RT
RT
RT
RT
HT
HT
No. of
Pts.
65
66
37
40
24
293
71
49
OR [%]
Control
46
35
53
50
10
35,5
36
48
OR [%]
with HT
66
72
83
85
43
57,6
54
83
Survival
benefit
n.d.
n.d.
n.d.
Yes
n.d
Yes
Yes
Ref.
57
58
59
60
26
33
61
62
Abbreviations: RT: radiotherapy; CT: chemotherapy; HT: hyperthermia; OR: overall response; Obs:
open-Iabel observational study; RCT: randomised controlled trial; n.d.: not defined; res: resistant
Table 8. Non-randomised clinical trials with RF capacitive coupled heating devices
Tumor site
Experimental
Cervix
Cervix
Breast
Breast
Breast
Colorectal
Colorectal
CT + HT
RT + HT
RT + HT
RT + HT
RT + HT
RT + HT
RT + HT
Control
RT
RT
RT
RT
RT
No. of
Pts.
23
40
9
24
13
48
117
OR [0/.]
Control
50
63
84
0
33
OR [0/.]
with HT
52
80
100
83
92
11
69
Survival
better
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
Ref.
63
64
20
21
65
22
23
7
Colorectal
Colorectal
Gastric
Gastric, adv.
Gliomas '111, IV
Liver (HCC)
Liver (Met)
Liver (HCC)
Liver (Met)
Lung (SCLC, SCLC)
Lung (NSCLC)
Oesophagus
Pancreas
Pancreas
Pancreas
Sarcoma
RT + HT
RT + HT
RT + CT +
HT
CT + HT
HT
CT + HT
HT + CT
HT
HT
HT
RT + HT
RT + HT
CT + HT
HT
HT
RT + HT
RT
RT
CT
CT
RT
-
101
14
21
55
20
-
71
100
89
n.d.
n.d.
Yes
24
25
35
33
36
48
80
73
45
-
39
43
-
20
313
22
25
-
56
31 (SD51)
31 (SD27)
75
63
36
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
25
38
27
37
66
67
36
67
31
25
68
69
70
31
74
Yes
Yes
Possibly
Abbreviations: HCC: hepatocellular carcinoma; Met: metastases: SCLC: small cell lung cancer.
NSCLC: non-small cell lung cancer; HT: hyperthermia; RT: radiotherapy; CT: chemotherapy;
adv:advanced
4.3. RF hyperthermia without combination with radio- or chemotherapy
Clinical trials with hyperthermia mostly have been performed in combination with radiation or
antineoplastic agents. But some first results from hypertherrnia trials with capacitive coupled
radiowaves with 13.56 MHz in the treatment of patients with primary tumours or metastases in the
liver, lung, pancreas and brain without combination with radio- or chemotherapy are promising.
Lung Cancer
In a prospective open-Iabel 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) induced by 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 CHTx 8.4 and 28.5 months after onset of DHT due to tumour-associated
symptoms (e.g. pain).
The median overall survival time (MST) of all patients was 14.0 months from 1't diagnosis of lung
cancer. From relapse after surgery or lst diagnosis of inoperable stage of disease the MST was 10.3
months. The 1- and 2-year survival rates from progression of disease were N% 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 lst diagnosis of disease was 34.4 months, and from
lst 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
8
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 month
[68].
In a prospective open trial with 46 patients with far advanced (non-resectable, relapsed or
metastasized) 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 regional RF-deep hyperthermia (13.56 MHz, Synchrotherm, Italycombined with
complementary therapies (proteolytic 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 begin of the multimodal treatment. Most patients experienced
essential improvement in quality of life (68% freedom of pain, 24% marked pain relief); 64%
improved appetite (thereof 24% normal appetite) over a long period of time, and reduction of jaundice
and ascites.
Gliomas
The primary aim of this study was to define the feasibility of radiofrequency 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 111, 27 patients with glioblastoma multiforme WHO grade IV)
were treated with RFDHT and Bosweillia, an inhibitor of leukotriene synthesis for inhibition of
peritoneal oedema. DHT was performed with a 13.56 MHz capacitive coupled RF-device. Patients
v%(ith 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 2: 50% were included. The study was designed as a prospective open-Iabel,
single-arm, mono-centred observational phase 11 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.
Results: DHT of brain tumours with RF-HT (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 tumour growth could be observed.
Prolongation of MST compared to historical controls and improvement of quality of live (EORTC,
QLQ-C30 questionnaires) is clinically significant. The survival time for WHO grade 111 was #
months and for WHO grade IV # months. The survival rates for WHO grade 111, and IV gliomas are
listed in the table 9 and 10.
Table 9: Survival probabillty: anaplastic strocytoma WHO grade 11 (n=9)
Time from
lst Diagnosis
Progression
Ist Hyperthermia
1-year±s.e.
100
100
78±14
2-year+-s.e.
75±15
75±15
65±17
3-year-+s.e.
75±15
60±18
65±17
4-year±s.e.
56±20
40±20
43±21
5-year-+s.e.
56±20
40±20
43±21
censored: 5 (56%); events: 4; s.e. = standard error
9
Tabl.: 10 survivel probability: Glioblastoma multiforme WHO IV(n=27)
Time from
1 st. Diagnosis
Progression
1st. Hyperthermia
1 -year±s.e.
70±9
55±10
39±10
2-year±s.e.
30±9
NA
13±7
3-year±s.e.
9±6
7±6
7±6
4-year±s.e.
9±6
7±6
0
5-year±s.e.
4±4
0
0
censored: 3 (11 %); events: 24; s.e. = standard error
Fig 2. Complete remission from anaplastic astrocytoma (WHO grade III)
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 8 and 27 MHz exhibit non-thermal
antineoplastic effects on cancer cells by direct electromagnetic coupling, f.e. with the cell membrane,
receptors or ion channels. This 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
tumours without increasing the temperature [72,73,74,75], 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 Stockholm [79] 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 A range [80].
Non-equilibrium thermal effects might be - at least partially - responsible for antineoplastic effects in
tumour 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 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.
Conclusions
Locoregional hyperthermia may contribute to therapeutic improvements in the treatment of cancer
patients. Randornised controlled phase 111 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 tumours, the locally advanced
10
cervical cancer, advanced head and neck tumours and glioblastoma, a survival benefit has been shown
in randomised controlled trials. In other tumours, such as local recurrent breast cancer and recurrent
melanoma an increase in local response nut 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
intraturnoural 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.
With respect to evidence-based gradings of clinical trials it should be mentioned that K. Benson et al.
(501 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.
11
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