Tumor Thermoradiotherapy Enhancement
Complex Research into Thermoradiotherapy Efficiency Enhancement due to Simultaneous Action of Ionizing Radiation and Heat on the Tumour and Development of Relevant Equipment
Tech Area / Field
- MED-DRG/Drug Discovery/Medicine
8 Project completed
Senior Project Manager
Yakusheva A A
MIFI, Russia, Moscow
- NPO ISTOK, Russia, Moscow reg., Fryazino\nVNIIEF, Russia, N. Novgorod reg., Sarov\nCancer Research Center, Russia, Moscow
- Universiteit Amsterdam / Academisch Medisch Centrum, The Netherlands, Amsterdam\nCentre Alexis Vautrin, France, Vandoeuvre\nErasmus University, The Netherlands, Rotterdam
Project summaryIn spite of the fact that lately an undoubted progress has been achieved in early diagnosis of malignant tumors and in possibilities of modern anticancer methods, the oncological patients mortality is still tremendously high. This demands to consider the improvement of malignant neoplasm’s control as a universal problem of primary importance.
Methods of treatment for malignant tumors can be conventionally pided into 3 basic groups:
– antitumor actions of local or regional type – surgical treatment, radiation therapy, targeted perfusion of antitumor chemicals;
– antitumor actions of a general type – systemic chemotherapy, hormonal therapy;
– auxiliary or indirect antitumor actions – immunotherapy, application of modifying (adjuvant) factors.
Until now none of these methods can meet in full the requirements of clinical practice. That is why, complex treatments are more and more often used nowadays for curing for many malignant tumors. This means successive or simultaneous application of several methods aimed to exploit the effect of synergism of their common influence on the malignant neoplasm.
For example, radiotherapy, one of the main methods for treating cancer which is used in all cancer clinics, has one large drawback – the sharp drop in efficiency when the tumor cells become hypoxic. This dependence of radiation effect on the oxygen status of the cell is tremendously important for cancer treatment, because development of hypoxic zones is one of the intrinsic features of tumor growth: the necessity for the tumor to slide away the surrounding tissues results in an elevated pressure in the tumor, which leads to the occlusion of many capillaries, decrease of blood perfusion, and thus, makes a significant number of the tumor cells deeply hypoxic. Mild hyperthermia, heating of the tumor to the temperature of 40 °C, is known to be an agent increasing tumor microcirculation. Elevated blood perfusion substantially increases tumor cell oxygenation and radiosensitivity, and, thus, is capable to help to overcome the mentioned above substantial drawback of radiation therapy.
The effect of heating on blood perfusion and, accordingly, on the tumor is complex. It is actually the mild heating, at the temperature of 40 °C, which leads to elevated perfusion. At higher temperatures hyperthermia has an opposite effect – it inhibits the blood flow, and this, in turn, leads to a rise of tumor temperature due to the lower intensity of tumor cooling by the blood flow. Being subjected to temperatures of 42-43 °C, cancer cells demonstrate inhibition of repair processes, and damage of cancer cells due to the heating itself. Thus, hyperthermia may produce three different anticancer effects: increase in tumor sensitivity to ionizing radiation through cell oxygenation, increase in cell sensitivity to radiation and to chemotherapeutic drugs through the change in their anabolism, and to kill cells directly. In the latter case it is supposed that the tumor temperature may be elevated to a higher extent than that of the normal tissue due to the methods of selective heating.
As a sequence, hyperthermia is nowadays one of the most perspective adjuvants increasing effectiveness of radiotherapy, especially in treatment of radio resistant malignant tumors [1, 2].
A most efficient way for heating tumor tissues is their irradiation with electromagnetic (EM) waves of high- or superhigh frequency and/or of the microwave range. EM oscillations are more preferable in comparison with other physical methods of providing higher temperature in a definite volume of the body due to absorption of the electromagnetic energy not only in surface, but also in deeply located biological tissues. Thus, the temperature growth in deep tissues occurs not only through heat transfer from the surface into the depth, but also as a consequence of EM energy absorption and transformation into heat in every point of the tissue volume being heated. Due to it, the problem of heat overloads (burns) of the skin can be eliminated by means of cooling the surface of the skin, while at the same time hyperthermical conditions in internal tumor tissues at the level of 42 – 44 °C can be easily achieved.
In case of combination of hyperthermia and radiotherapy (their successive application) the radiotherapy effectiveness increases in the average as much as 1.5 times. This effect has been confirmed by many international randomized studies carried out in Belarus, Russia, USA, Germany, Italy, England, The Netherlands, France and others [see e.g. 1, 2, 3, 4, 5, 6, 7]. These results were obtained by means of existing at present techniques and methods in conducting hyperthermia and radiotherapy, which admit only a successive order of external radiation and heating procedures.
At the same time, it has been shown in experiments on mice that when radiation and mild heating were conducted simultaneously the effectiveness of radiation increases as much as 2.5 – 4 times . This effect is linked to the rise of tumor oxygenation caused by mild heating at the time of radiation .
Consequently, the radiation destruction of cancer cells due to the Oxygen-effect will be the most in case the tumor would be subjected to Simultaneous ionizing Radiation and mild Heating (SRH) [2, 8, 9]. It should be noted that conventional high temperature hyperthermia being performed out of radiation successively with SRH, may result in an additional lethal damage of cancer cells.
There are three principle unsolved problems which prevent from putting into clinical practice this promising SRH technology:
– deficiency of practically usable in clinics hyperthermic and radiation equipment permitting simultaneous selectively heating and external ionizing irradiation of the tumor;
– long duration of the hyperthermia procedure which at present makes up 40–60 minutes, while the time period for an external radiation treatment procedure, accomplished by means of a very expensive and intensively exploited equipment, can not last longer than 10-15 minutes;
– absence of well developed clinical technologies for conduction of SRH.
This Project proposes solution of the two first problems, as well as gain additional basic knowledge about biochemical processes proceeding in the tumor sells subjected to SRH influence. These results of the Project may open the way to solve the third, clinical problem too.
The following works (stage by stage) are to be performed:
1. Creation of technical means, providing the possibility of experimental investigations and clinical testing of SRH:
– Development of a unit for experimental investigation of SRH impact on malignant and normal cells in vitro and in vivo.
– Development of simple and convenient in use microwave applicators for highly directed local and regional hyperthermia through which external high energy ionizing irradiation of superficial and deeply located tumors is to be performed; the applicators should neither absorb noticeably the ionizing radiation nor distort its homogeneity of distribution in the volume being irradiated, and must stand without damage high doses of high energy radiation.
– Experimental investigation of the developed applicators under conditions of real high energy radiation, produced by X, - rays and electrons.
– Development of a computerized system for planning, precision ionizing radiation targeting and control of the simultaneous radiotherapy and hyperthermia procedure.
2. Study and optimization of the time-temperature regimens during the SRH procedure with the aim to provide substantial reduction of the heating exposure time required at SRH sessions, and elaboration of proposals for clinical testing of the SRH treatment modality:
– Comparison of the effect of concurrent and sequential heating and ionizing radiation on several tumor types implanted in mice and rats.
– Investigation of physiological parameters of tumor and normal tissue of mice and rats subjected to SRH in vitro and in vivo.
– NMR spectroscopy investigations of the intra-cellular mechanisms of radiosensitivity increase due to SRH precisely at the moment of irradiation on cultures of several modes of tumor and normal cells in vitro, and on tumors, implanted in mice and rats, in vivo at different time-temperature regimens.
– Investigations of different time-temperature SRH regimens with the aim to reduce the heating time needed for effective SRH.
– Search for and investigation of remedies increasing the heat sensitivity of malignant cells.
– Elaboration of optimal temperature-time schedules of SRH procedures for various strains of experimental tumors and proposals for clinical testing of the SRH treatment modality.
The proposed Project is to be fulfilled by scientists and engineers high educated and experienced in the fields the Project deals with from: MEPhI (Moscow) – precision target aiming and dosimetry of ionizing radiation; VNIIEF – All-Russian Research Inst. of Experimental Physics (Sarov) – development of methods and algorithms for calculation of heat and electromagnetic fields distribution at irradiated heterogenic biological tissues; applicator testings for stability to high energy radiation; SRPC “Istok” (Fryazino, Moscow region) – development and testing of HF and SHF EM applicators, equipment and devices for heating under conditions of hard ionizing radiation; RCRC RAMS (Moscow), and invited by SRPC “Istok” specialists in cellular biology – radiobiological investigations.
The Project will provide for weapons specialists from MEPhI, SRPC “Istok” and VNIIEF opportunities to redirect their efforts to peaceful activities and promote their integration into the international scientific community.
Foreign specialists from leading oncological institutions in The Netherlands, France and USA gave their agreement to collaborate on the Project with the Russian team, providing information exchange and comments to technical reports, conduction of joint seminars and workshops.
Namely they are: Jan D.P. van Dijk, Ph.D. – Head of Radiotherapy Dept., Academic Medical Centre, University of Amsterdam, The Netherlands; Christian Marchal, M.D., Ph.D., Head of Radiotherapy Dept., Regional Oncology Centre Alexis Vautrin, Nancy, France; Gerard C. van Rhoon, Ph.D., Head of Hyperthermia Lab., Dept. of Radiation Oncology, Daniel den Hoed Cancer Center, University Hospital Rotterdam, The Netherlands; Eduardo G. Moros, Ph. D., Associate Professor Radiation Oncology Center, Washington University School of Medicine, USA.
Expected results of the Project should be:
– new basic knowledge of the kinetics of malignant and normal cells’ reaction on simultaneous ionizing and temperature impacts;
– development of new equipment and techniques for clinical testing of the SRH technology;
– motivated proposals for clinical testing of a new efficient modality of treatment for malignant diseases: simultaneous thermoradiotherapy (SRH).
1. N.N. Alexandrov, N.Ye. Savchenko, S.Z. Fradkin, E.A. Zhavrid, 1980, Application of hyperthermia and hyperglycemia in treatment of malignant tumors, "Medizina", Moscow, (in Russian).
2. Field, S.B., & Hand J.W., editors, 1990, An Introduction to the Practical Aspects of Clinical Hyperthermia, Taylor & Francis, London-New-York.
3. J. Overgaard, D. Gonzalez-Gonzalez, M.C.C.M. Hulshof, G. Arcangeli, O. Dahl, O. Mella and S.M. Bentzen, 1995, Randomised trial of hypertermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma, The Lancet, v. 345, p.p. 540 –543.
4. C. Vernon, J. Hand, S. Field et al., 1996, Radiotherapy with and without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized control trials, Int. J. Radiation Oncology, Biology, Physics, v.35, No.4, 731-744.
5. A.S. Mavrichev, 1996, Pochechno-kletochny rak (Renal cell carcinoma), BelCNMI, Minsk, 295 p., (in Russian).
6. M. Sherar, F.F. Liu, M. Pintilie et al., 1997, Relationship between thermal dose and outcome in thermoradiotherapy treatments for superficial recurrences of breast cancer: data from a phase III trial, Int. J. Radiation Oncology, Biology, Physics, v.39, No.2, 371-380.
7. J. Van der Zee, D. Gonzales-Gonzales, G. van Rhoon, J.D.P. van Dijk, W van Putten, A. Hart, 2000, Comparison of Radiotherapy alone with Radiotherapy plus Hyperthermia in locally advanced pelvic tumors. The Lancet, v. 335, No. 9210, p.p. 1119-1125.
8. M.R. Horsmann, J. Overgaard, 1995, The influence of nicotinamid and hyperthermia on the radiation responce of tumor and normal tissues. Book of Abstracts, 15th Annual Meeting of ESHO, Wadham College, Oxford, UK, 3-6 September 1995, p.12.
9. M. R. Horsmann and J. Overgaard, 1997, Can mild hyperthermia improve tumor oxygenation? International Journal of Hyperthermia, 13, No. 2, p.p. 141-148.
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