Marwan Al-Akasheh, MB, BS, FACP

Introduction

Oncothermia preclinical studies

1. Distribute the energy in the tissue where the energy could be applied on the most
optimal way, do not allow the homogeneous heating of the area. The target of
oncothermia is the cellular membrane. Keeping the current in the extracellular matrix
the energy heats up only this electrolyte, and a heat-flow starts from the extra- to
intra-cellular regions through the membrane. This heat-flow accompanied by different
ionic flows and water transport, changes the Hodgkin-Huxley equilibrium, the
membrane became more transparent, and at the end destroyed 65.
These points are realized, and called this procedure electro-hyperthermia or oncothermia 18,61.
Many theoretical considerations were performed to validate this idea55, 61. Also the modern
fluctuation analysis (fractal-physiology) supports the oncothermia 63.
To clarify the effect of oncothermia alone and in comparison with classical heating methods
some preclinical research was made. The experimental setup made possible to keep the
conditions for both heating methods identical, heating in the classical way (outside plan-
parallel heaters) and in the oncothermia way (outside plan-parallel condenser electrodes) Fig.
1. The oncothermia was performed by a specially developed laboratory device for the in vitro
and in vivo experimental purposes, Fig. 2.

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 Hypertherm
Fig. 3. Experimental setups for classical Fig. 4. The laboratory device for in vitro
hyperthermia and oncothermia and in vivo oncothermia experiments
measurements
Oncothermia is selective by the higher conductivity and higher permittivity of the
extracellular matrix of malignant tissue (Szasz et al., 2008). The high complex dielectric
constant is effective in the microscopic level as well. In coculture experiments the healthy
fibroblast remain intact, while the aggressively malignant melanoma cells (A431 cell line) are
destroyed (Fig. 5) (Brunner, 2007)

Fig. 6. Selectivity in vitro experiments: only the aggressively malignant A431 cells are
destroyed in a coculture with non-malignant fibroblasts. Sampling: 24h after the treatment,
crystal-violet staining. (Brunner, 2007)
The constrained thermodynamic transport destabilizes the cell-membrane, increases its
permeability and can induce its bobbling and distortion (Szasz et al., 2003). These are high
efficacy factors favor oncothermia over its temperature-equivalent hyperthermia counterpart,
Fig. 7.

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 Fig. 8. Lethality
comparison of onco-
thermia with classic
hyperthermia in vitro
(native microscopic
images of HL-60
leukemia cells)

The setup made possible a fine temperature control, which allowed to keep the heating,
keeping and cooling dynamist also identical, Fig. 9. This makes identical heat-shock protein
induction by the temperature changes. The temperature dependent equality was controlled by
luciferase transient transfected HEK293 cell lines (Andocs et al., 2008)

Fig. 10. The dynamics of the heating and cooling is also well controlled for comparison of
the two heating methods.
Change of adherent connections (E-cadherin and β-catenin) are indicators of the gain of the
social signals promoting the apoptosis (Szasz et al., 2008), (Bremnes et al., 2002).
Remarkable change could be observed on beta-catenin dynamic development by time after
the treatment, Fig. 11. on HepG2 human hepatocellular carcinoma cell-line. This considerable
change after 24 hours of the treatment is sharply different from hyperthermia on the same
temperature, and supports the other observations of the non-temperature dependent processes
(Szasz, 2008). The sudden regrouping the beta-catenin and its enrichment at the cell-nuclei
could be an indicator of apoptosis (Gijn et al., 2001).
Temperat

44
43
Hyperthermia
42
41
re (oC)

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 Fig. 12. Development of β-
catenin by time elapsed
after the treatment in
comparison of untreated
and hyperthermia as well as
oncothermia treated U
samples. Sampling: 1h, 3h,
24h after the treatment;
After
(Immuno-fluorescent
microscopic images, red: β-
treatment:
catenin, blue: cell nuclei)

1 hour

Detecting the double strains of DNA (DAPI staining, Fig. 13.) and measuring the enzymatic
labeled strain-breaks of DNA (TUNEL-FICT, Fig. 14. ) the apoptosis is highly likely in
oncothermia, while at identical temperature in classical hyperthermia the necrosis is
preferred.

3 hours

Fig.15. DAPI staining (stains the double Fig.16. TUNEL-FITC staining (enzymatic
strains of DNA only) label of the strain-break of the DNA)

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The in vivo experiments well support the in vitro results. The excellent focusing of
oncothermia can be proved by the temperature measurement in the tumor and the surrounding
healthy muscle.
Xenograft tumor-models were used to prove the effect in vivo. Human colorectal carcinoma
cell-line (HT-29) was induced by subcutaneously injected at the femoral region on both sides
of female nude mice with 6 x 106 cells in 0.1 ml of serum free medium, symmetrically when
the animals were 6-8 weeks old and their weighs were 22-25g. 18 days after the tumor
inoculation, experiments started on anesthetized animals. For the experiment we only used
the animals which developed their tumors symmetrically and approximately the same size
(e.g. Fig. 17.).

Fig. 18. Symmetrically developed tumors on nude

mouse.

Two kinds of treatments were performed: local classical hyperthermia and oncothermia (Fig.
19.) Both of the treatments were controlled by accurately measured intratumoral temperature
with fluoro-optical method.
Fig. 20. Experimental
setups of hyperthermia and
oncothermia

The method to calculate the killing rate of the treatments is a morphological comparison
based on the observed pathological differences. The living part being in intensive
proliferation microscopically could be easily distinguished from the necrotic part containing

Hyperthermia treatmen
the dead tumor cells. We compared the area-change of the dead part of the control and treated
tumor originated from the same animal. The differences are significant, (Fig. 21.).

Fig. 22. The macro-evaluation of the efficacy of oncothermia in comparison to the

hyperthermia in HT29 tumor xenograft. Change of the areas of dead and vivid parts in

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 percentage of the untreated control on the same experimental animal (data average of 3
animals each), Similar experiments were carried out with the same results for A431 human
epidermoid carcinoma xenograft model and GL261 murine glioblastoma model
Comparison of hyperthermia and oncothermia combined both methods with mitomycin-c
(MMC) single dose chemotherapy in vivo at tissue and cellular level using histological
examinations is shown on Fig. 23. HT29 human colorectal carcinoma cell line derived
xenograft tumor model in nude mouse. 2 animals for hyperthermia (42ºC) + 3mg/kg MMC
ip. (30min before the treatment); and 2 animals for oncothermia (42ºC) + 3mg/kg MMC ip.
(30min before the treatment).

A) B)
Fig. 24. Investigating the difference of the effects of i.p. administered Mitomycin CA)The
cellkilling is relative to the control tumor on the same animal. (Two-two animals was
measured with double tumors on each for control. ) B)Hematoxilin-eosin stained microscopic
images of tumor samples
The temperature dependence was also investigated (Szasz, 2008). The same temperature
application of the two thermal treatments was tried together with the only field application
(cooled back) case (Fig. 25.). It was clearly shown the advantage of oncothermia where the
electric field has significantly higher effect as the temperature as well as they have good
synergy in cell-killing process (Fig. 26.).
method (%)

Fig. 27. A sample of the temperature Fig. 28. Comparison of cell-killing effect

70
pattern of hyperthermia and oncothermia of hyperthermia and oncothermia at

45
at different temperatures. different temperatures.

44 Clinical studies

43 60
Numerous clinical studies show the efficacy of hyperthermia in oncology. Both the radiative and
capacitive hyperthermia solutions have important results, but their control many times has serious

60
C)

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problems. For example, results of a cervix clinical study in combination with radiotherapy, (van der
Zee, 2000) was a breakthrough in 2000. However, later the results could not be repeated,
(Vasanthan et al., 2005), and a temperature reference point was in search, (Fatehi et al., 2006).
The definite problem is always the appropriate energy targeting and its adequate control, which
makes the sentence: “the biology is with us, the physics is against”, (Nielsen et al., 2001), or “the
physiology is against” (Osinsky, 2004)
A spectacular case is shown (Fig. 29., (Renner, 2007)). The 67 year old patient had complete right
ophthalmoplegy due to an inoperable squamous epithelium carcinoma in sinus sphenoidalis.
Radiation was applied (54 Gy) with 6 oncothermia simultaneously. The result is complete
remission. The importance of the case is its near-eye application, but without the eye was involved.
(Note: the treatment of the eye is strictly contraindicated!)

(recen

Fig. 30. Case example of oncothermia.

The near-eye treatment (38 y, female; Non-Hodgkin Lymphoma, stage IV., combination with
chemotherapy “Bendamustin”) is shown also (Fig. 31. Herzog, 2008).

Fig. 32. Case example of oncothermia applied for non-Hodgkin lymphoma on eye-lid.
Other case report shows results of esophagus carcinoma of 54 y old male patient (fig. 33.,
(Sahinbas, 2006)) After multiple chemotherapies, surgery and 50 Gy radiotherapy the tumor was
progressively grown, blocking the food-passage. After 6 oncothermia (monotherapy) treatments was
partial, after 12 was normal food passage, no tumor-tissue was found by biopsy.

01.08.01.

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Fig. 34. Lumen-block (01.08.01.) before the oncothermia. After six oncothermia treatments
(29.11.2001) and after 12 oncothermia (17.01.2002) the normal food passage was reestablished.
Remarkable amount of clinical data are available to indicate the oncothermia effect in humans. The
present collection shows some of the retrospective clinical results. These are single arm, open label
studies for intention-to-treat (ITT) population, dominantly for the patients in late/advanced stages,
where the conventional methods were fallen. Mostly the survival rate was the studied endpoint. The
inclusion criteria was the inoperable and/or in progression after chemo- and/or radio-therapy.
Exclusions were only the well known contraindications of the hyperthermia: metallic implants in the
treated volume, electronic supports (like pacemaker), massive ascites, inflammatory lesions, etc.
The possible negative biases were connected to the retrospective data collection. Negative is the
missing randomization. Having no prospective control arm comparison is also negative.
(Comparison with large studies and databases as well as local historical data was made.) The
treatments were made on a voluntary basis for ITT population, which was negative bias as well.
Positive bias was the selected very advanced patient-population. Also positive is the missing “trial
psycho-attention” and the entirely regular treatment conditions (no extra care is given).
The primary endpoints of the studies were always the survival rate, which was evaluated by regular
descriptive biostatistics and log-rank survival test.
The treatment had minor number of erythema (<8%). No significant subcutaneous fibrosis as well
as no other toxicity was observed except for the usual toxic reactions of the complementary applied
conventional treatments (radio- and/or chemo-therapies). Patients reported (subjective) decrease of
adverse effect of parallel conventional therapies. Most patients reported decrease in pain and other
subjective symptoms and improvement in their general well-being.
Remarkable amount of clinical studies are available to indicate the oncothermia effect in humans. It
is commonly used for such a complex and very frequent tumors like lung, liver, pancreas, brain,
gastrointestinal, gynecological, etc. The retrospective data are compared to the large databases
((Seer, 2000) and Eurocare), having possibility to see the position to the best available data in a
huge average. The oncothermia challenge is its small fraction only of the overall survival.
Oncothermia is applied when other treatments fall, consequently the patients with long overall
survival could have not observable life-elongation, even if oncothermia was effective. The
aggressive disease with short survival is a chance to indicate the efficacy. For these reasons we
compare the 1st year survivals rate only (see fig 8.). In this sense oncothermia is indicated as a
feasible, effective method (Szasz et al., 2005).

Patient number Oncothe

# Localization
SEER Eurocare Oncothermia 1st year

1 Brain glioma 28970 14452 140 90.63

Fig. 2. Comparison
Colo-rectalof the first-year 242920
survival rates127406
of various cancers with 218 20.5
the large databases
Improvement of the first-year survival percentages of oncothermia (advanced patients) compare to
3 Esophagus 18302
SEER and Eurocare data weighted average.
18231 12 34
4 Ovary 39383 22929 27 51.1
5 Corpus uteri 68271 22509 9 15
6 Kidney 38270 8 23683 39 22.2
120
)

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7 Liver 12696 9041 25 250.9
The median of overall survival time is also gained in most of the localizations, despite of the only
advanced cases in oncothermia treatments, (Table ).

Patient
survival-timesnumber
Table . Comparison of median of overall
of various localizations.

# Localization SE
SEER Oncothermia
me
1 Brain glioma 28970 140 11
2 Colo-rectal 242920 218 45
3 Esophagus 18302 12
Oncothermia have large collection of retrospective data. Some of these collected data from such
difficult localization, like brain-gliomas. The most important publications on brain treatments were
9
4 Ovary
on prestigious conferences like ASCO (Hager 39383 27
et al., 2003), (Hager et al., 2008), ICACT (Szasz, 31
2004), ESHO (Sahinbas 2002), ICHS (Hager 2004), (Kleef et al., 2004), ICHO (Hager et al., 2004),
5 Corpus
(Sahinbas et al., 2004),uteri
and others (Sahinbas, 68271 9 2006). The 12
2004), (Sahinbas et al., 2005), (Fiorentini,
median survival times results are significantly higher than measured in other studies as well as the
6 Kidney
age-adjusted 38270
survival is significantly higher (Fig. 35.). 39 51
7 Liver 12696 25 7
8 Lung
25
268106 Brain-gliomas (a 258 9
9 Pancreas 47368 99 7
10 Prostate 243451 18 83
11 Soft-tissue 11256 16 88
12 Stomach SEER (Surveillance, 42813 Epidemiology, 68 and End 10 R
MRC (Medical Research Council, Brain Tumor
20 RTOG (Radiation therapy Oncology Group, RT
Fig. 36. Median survival of oncothermia treated brain glioma patients, compared to the large
Median survival (m)

studies and databases. EORTC(European

(RTOG, EORTC, RT, MRC, SEER))(Szasz Organization
et al., 2004.). for Research
To see more evidences TMZ = Temizolomide
we show the retrospective data ofPCV = Procarbazine+CCN
independent clinics, having the same
oncothermia protocol (Fig. 37.). The data are well correspond to each other and significantly higher
than the data of the large international databases.

14.6
15
12.1

10
20
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 Brain glioma 1y survival [%]

Brain glio
n=28970 n=14452 n=29 n=35 n=140
100
86.2

first year survival [%]

80 73.8 71.7

60
45.4
37.8
40

n=28970
20
SEER Eurocare HTT Clinic BioMed Clinic

n=15
Groenemeyer
Clinic

Fig. 38. The median survival and the first year survival in comparison with different clics, having

25
the same oncothermia treatment protocol.
The metastatic liver tumor is a very complicated issue due to the effective cooling of the large blood
flow and the sensitivity of the organ due to the chemo-toxicity from previous treatments. Our results
are also exceptionally good for that organ. The colorectal liver metastasis was the topic of four
different studies (Hager et al., 1999), (Ferrari et al., 2007), (Fiorentini et al., 2006), (Panagiotou et
al.,2005). The sensitivity of the liver on the chemotherapy in advanced cases (when the other
chemo-treatments were unsuccessful) is well observable on the combined treatment compared to the
oncothermia monotherapy, Fig. 39. (Hager et al., 1999).

Fig. 40. Colorectal cancer

liver metastases
retrospective clinical study,
(n=80).

15
11.49
Application of chemotherapy in second line gains the response rate significantly higher than was in
the first line without oncothermia, Fig. 41. (Panagiotou et al.,2005). 11.3

Compa
100% overall

Fig.42. Colorectal cancer liver metastasis study first/second line” Therapy (n=15), , Second line 80%
was combined with oncothermia, and reached much higher remission rate than the first line had.

5 60%
10
Treatment CRC liver
SEER RTOG m
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Both the liver and the colorectal tumors were treated in two independent hospitals, having identical
therapy protocols. The results are supporting the significant gain of the historical results, Fig. 43.
Liver CA 1y survival [% ] Colorectal CA 1y survival [% ]
n=12696 n=9041 n=13 n=12 n=242920 n=127406 n=175 n=40
90
85 85.7
75.0
75 69.2 81.4
65 80
55
72
45 68.9
70
35
24.5
25 16.5
15 60
SEER Eurocare HTT Clinic Peterfy Hospital SEER Eurocare HTT Clinic Peterfy Hospital

Fig. 44
The pancreas carcinoma is a rapid and aggressive disease, and not too many conventional
hyperthermia results can be found in this location, (Hager et al., 1994). Oncothermia results
presented on ASCO, (Hager et al., 2002) and other conferences (Dani et al., 2003.), (Dani A, 2004)
are significantly improving the achievements of the conventional treatments. Results were repeated
in six different clinics in two countries (Fig. 45), and so the gain definitely made on statistical
evidences.
Fig. 46. Comparison of six
independent clinics treating
with the same oncothermia
protocol to the SEER and
Eurocare databases.

The lung is also a complicated organ for hyperthermia because of the permanent cooling-ventilation
of the breathing. Oncothermia, due to the non-equilibrium approach, is an excellent treatment for
that as well, (Hager et al., 1999), (Dani, 2003), (Dani et al., 2004), Fig. 47.

NSCLC 1y survival [% ]
Fig. 48. Kaplan-Meier survival plot
for overall survival of advanced Lung
n=268106 n=127487 n=197 n=61
patients (n=258 pts.).
85
75 67.2
64.0
65
55
45
36.1
35 29.7
25
SEER Eurocare HTT Clinic Peterfy Hospital

60
%]

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 Conclusion

In vitro and in vivo experiments, as well as the human clinical studies strongly support this newly
developed technology. Our present work shows a definite advantage of oncothermia over
hyperthermia.

The non-temperature dependent factors increase the efficacy and enhance the applicability of the
treatment. With oncothermia such sensitive organs like the brain, liver and lung could be treated
successfully.

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