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Oncothermia Editorial By Dr Marwan Al-Akasheh_ MB_ BS_FACP

Oncothermia Editorial By Dr Marwan Al-Akasheh_ MB_ BS_FACP

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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 planparallel 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 hyperthermia and oncothermia measurements Fig. 4. The laboratory device for in vitro and in vivo oncothermia experiments 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 oncothermia 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 42

Hyperthermia

re (oC)

41 40 39
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Fig. 12. Development of βcatenin by time elapsed after the treatment in comparison of untreated and hyperthermia as well as oncothermia treated samples. Sampling: 1h, 3h, 24h after the treatment; (Immuno-fluorescent microscopic images, red: βcatenin, blue: cell nuclei)

U

After treatment: 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 strains of DNA only) 4

Fig.16. TUNEL-FITC staining (enzymatic 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 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.).

Hyperthermia treatmen

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 5
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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.).

Fig. 27. A sample of the temperature pattern of hyperthermia and oncothermia at different temperatures.

C) method (%)

45 44 43 42

70 60

Fig. 28. Comparison of cell-killing effect of hyperthermia and oncothermia at different temperatures.

Clinical studies

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 6
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60

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 # Localization SEER

Oncothe

Eurocare Oncothermia 1st year

1 Brain glioma 28970 14452 140 90.63 242920 127406 218 20.5 Fig. 2 Comparison of the first-year survival rates of various cancers with the large databases . Colo-rectal Improvement of the first-year survival percentages of oncothermia (advanced patients) compare to 3 Esophagus 18302 18231 12 34 SEER and Eurocare data weighted average. 4 Ovary 39383 22929 27 51.1 5 Corpus uteri 68271 22509 9 15 6 Kidney 38270 8 23683 39 22.2 Medics Index Member LIVE PRESS Page www.medicsindex.net 7 Liver 12696 9041 25 250.9

120

)

The median of overall survival time is also gained in most of the localizations, despite of the only advanced cases in oncothermia treatments, (Table ). Table . Comparison of median Patient number of overall survival-times of various localizations.

#

Localization

SEER

Oncothermia

SE me

than the data of the large international databases.

Median survival (m)

1 Brain glioma 28970 140 11 2 Colo-rectal 242920 218 45 Oncothermia have large collection of retrospective data. Some of these collected data from such 3 Esophagus 18302 12 9 difficult localization, like brain-gliomas. The most important publications on brain treatments were on prestigious conferences like ASCO (Hager et al., 2003), (Hager et al., 2008), ICACT (Szasz, 31 4 Ovary 39383 27 2004), ESHO (Sahinbas 2002), ICHS (Hager 2004), (Kleef et al., 2004), ICHO (Hager et al., 2004), (Sahinbas et al., 2004),uteri (Sahinbas, 68271 2004), (Sahinbas et al., 2005), (Fiorentini, 2006). The 12 5 Corpus and others 9 median survival times results are significantly higher than measured in other studies as well as the age-adjusted survival is significantly higher (Fig. 35.). 6 Kidney 38270 39 51 7 Liver 12696 25 7 8 Lung 268106 258 9 25 9 Pancreas 47368 99 7 10 Prostate 243451 18 83 11 Soft-tissue 11256 16 88 SEER (Surveillance, Epidemiology, and End 10 R 12 Stomach 42813 68 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 studies and databases. EORTC(European Organization for Research (RTOG, EORTC, RT, MRC, SEER))(Szasz et al., 2004.). To see more evidences we showTemizolomide PCV = Procarbazine+CCN TMZ = the retrospective data of independent clinics, having the same oncothermia protocol (Fig. 37.). The data are well correspond to each other and significantly higher

Brain-gliomas (a

15 12.1 10
9

14.6

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20

Brain glioma 1y survival [%]
n=28970 n=14452

100
first year survival [%]

Brain glio
n=29 n=35 n=140

86.2

80 60 40 20

73.8

71.7

45.4

37.8

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

n=28970

SEER

Eurocare

HTT Clinic

BioMed Clinic

n=15
Groenemeyer Clinic

25

15
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).

11.49

11.3

100% 80% 60%
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Compa overall

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

5

Treatment CRC liver m SEER RTOG

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 [% ]
n=12696 85 75 65 55 45 35 25 15 SEER Eurocare HTT Clinic Peterfy Hospital 16.5 60 SEER Eurocare HTT Clinic Peterfy Hospital 24.5 70 69.2 n=9041 n=13 n=12 75.0 80 72 68.9 90 n=242920

Colorectal CA 1y survival [% ]
n=127406 n=175 85.7 81.4 n=40

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 [% ]
n=268106 85 75 65 55 45 35 25 SEER Eurocare HTT Clinic Peterfy Hospital 36.1 29.7 64.0 67.2 n=127487 n=197 n=61

Fig. 48. Kaplan-Meier survival plot for overall survival of advanced Lung patients (n=258 pts.).

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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References
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58. Szasz, A., Sahinbas, H. (2004). Agydaganatok elektro-hipertermiája. Retrospektiv klinikai vizsgálat 155 német beteg bevonásával, Presentation on the Annual Congress of Hungarian Oncologists, Budapest, 2004. 59. Szasz, A., Sahinbas, H., Dani A. (2004). Electro- hyperthermia for anaplastic astrocytoma and gliobastoma multiforme ICACT 2004, Paris. 60. Szasz, A., Szasz, N., Szasz, O. (2004). Hyperthermia in der oncology: eine aktuell beforschte behandlungsmethode,, Integrative Onkologie, 1:19-27. 61. Szasz, A., Szasz, O., Reinicke, A. (2008). Principles of Oncothermia, Springer Verlag, (contracted-work, book in preparation). 62. Szasz, A., Szasz, O., Szasz, N. (2001). Electrohyperthermia: a new paradigm in cancer therapy, Wissenschaft & Forschung, Deutsche Zeitschrift für Onkologie, 33:91-99. 63. Szasz, A., Vincze, Gy. (2006). Dose concept of oncological hyperthermia: heat-equation considering the cell destruction, Journal of Cancer Research and Therapeutics, 2:171-181. 64. Szasz, A., Vincze, Gy., Szasz, O., Szasz, N. (2003). An energy analysis of extracellular hyperthermia, Magneto- and electro-biology, 22:103-115. 65. Szasz, O., Andocs, G., Szasz, A. (2008). Thermally induced effects in oncothermia treatment, Symposium on Biophysical Aspects of Cancer, Electromagnetic mechanisms, (in memoriam H. Froelich), Prague, 1-3. July, 2008, submitted to Electrom. Bio. Med. 66. Szendro, P., Vincze, G. , Szasz, A. (2001). Pink-noise behaviour of biosystems; Eur.Biophysics J. 30:227-231. 67. Szendro, P., Vincze, G., Szasz, A. (2001). Bio-response to White Noise Excitation; Electro- and Magnetobiology 20:215-229. 68. Urano, M., Douple, E. (Eds.) (1989). Hyperthermia and Oncology, Vol.2. Biology of thermal potentiation of radiotherapy, VSP BV Utrecht The Netherlands, VSP BV Utrecht The Netherlands. 69. van der Zee, J., Gonzalez, G. D., van Rhoon, G.C., van Dijk, J.D., van Putten, W.L., Hart, A.A (2000).: Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumors: a prospective, randomised, multicentre trial. Dutch Deep Hyperthermia Group., The Lancet 1;355(9210):11191125. 70. Vasanthan, A., Mitsumori, M., Part, J.H., Zhi-Fan, Z., Yu-Bin, Z., Olynychenko, P., Tatsuzaki, H., Tanaka, Y., Hiraoka, M. (2005). Regional hyperthermia combined with radiotherapy for uterine cervical cancers: a multiinstitutional prospective randomized trial of the international atomic energy agency, Int. J. Rad. Oncol. Biol. Phys. 61:145-153.

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