Setembro de 1999
Marina Del Rey, Los Angeles, CA, USA.
THERMORADIOTHERAPY FRACTIONATION IN THE CLINICAL
TREATMENT OF MALIGNANT TUMORS
Bicher, H., M. D.
Valley Cancer Institute, Los Angeles, CA, U.S.A
Hyperthermia has been proven to increase the response of malignant tumors to radiation therapy in both experimental animal tumors and the clinical treatment of human cancer. Based on our multi-year experience, first in re-treatment of previously radiated fields that necessitated the use of low dose radiation fractions as adjunct to the heat treatments, and then progressively applying the encouraging results obtained to areas treated "de novo" and eventually to situations allowing a potentially curative intent, treatment protocols have been devised and tested that yield positive preliminary data showing superior tumor response rates and less side effects when compared with historical controls at our Institute.
The hyperthermia part of the protocol extends the number of heat treatments to correspond to the number of radiation-fractions, as each hyperthermia treatment proceeds or follows each radiation treatment in close time proximity. The number of hyperthermia treatments therefore varies from 25-50 per course for each treated field.
The radiation protocol consists of progressively decreasing daily doses of radiation therapy combined with the daily hyperthermia treatments. Typically the treatment is started at a daily dose of 180cGy gradually reduced to 100cGy protracting a typical radiation therapy treatment course from 5000cGy in five weeks to 5000cGy given in over eight weeks; or 7000cGy in seven weeks to 7000cGy in 14 weeks. According to the ELLIS TDF formula, this results in a 15% or 25% reduction of the effective radiation dose. The total dose is of course adapted to the clinical situation.
The following Conclusions are drawn:
CONCLUSIONS
Protracted Hyperfractionation
Decreases the radiation dose by 15% and 24%.
Decreases the side effects of XRT (no diarrhea, fistula or pneumonitis in PH cases)
Allows for more combined XRT-Hyperthermia treatments
Increases the effectiveness of the combined treatment in superficial and deep tumors.
Question: What is the lowest radiation dose needed to potentiate Hyperthermia?
THERMORADIOTHERAPY IN BREAST CANCER – THE
TREATMENT OF LOCALIZED INFLAMMATORY
RECURRENCE
Bicher, H., M. D.; Wolfstein, R., M. D.;
Keen, T., M. N.; Carter, S., Ph. D.
Valley Cancer Institute, Los Angeles, CA, U.S.A
Thermoradiotherapy is well established as a primary or adjunct treatment of mammary adenocarcinoma. Results in our series since 1984, encompassing 142 treated patients show a 90% response rate of which 72% are complete responses. However, when local treatment is done in the face of disseminated disease, the response rate is markedly reduced. Response rate increases with the number of hyperthermia treatments.
Localized inflammatory breast cancer, usually extending from the affected breast or mastectomy site to the chest wall is a rapidly lymphatic spreading form for cancer, usually resistant to radiation or chemotherapy, and prone to rapid dissemination.
This presentation reports on a phase 1 clinical trial involving 71 fields in 16 patients. Each field received 2000-4000cGy of external beam bolused radiation combined with 25 or more hyperthermia treatments given within one hour of the radiation.
Response rate was gratifying. 90% of the fields responded to the combined treatment, with complete disappearance of the inflammatory process in 81% of the treated areas. There was only one recurrence in the areas of complete response while areas that responded partially showed regrowth within 3 months of treatment. Side effects were minimal, in the form of 6 first degree superficial burns. There was no correlation between the response rate and the radiation dose.
These preliminary results show that thermoradiotherapy should be considered as a treatment modality for inflammatory breast cancer.
HYPERTHERMIA OF TUMORS AT THE 0.88 MHz
Brusentsov, N. A. 1, Jurchenko, N. Y. 1, Sergeev, A. V. 1,
Shumakov, L. I. 2
1.Russian Cancer Research Center RAMS; Russia, Moscow
2. Russian Radiotechnical Research Institute; Russia, Moscow .
Ferrimagnetic fluids (FFs) saturation magnetization from 3.0 to 7.4 kA/m) that was prepared from six batches of dextran-ferrite (DF) specific saturation magnetization 21 A × m 2/kg, specific power absorption rates 420 W/g Fe, keeping for six yars at –5 oC, possess dynamic viscosity 8.6 mPa × c -1. DF acute toxicity was studied in normal 36 male mice C57Bl/6j, 180 mongrel male mice, in normal 30 BDF 1 female mice, in normal 30 F 1 (CBAxC57Bl/6j) female mice in two modes of administration: intravenous and intraperitonial; in 5 mongrel male rabbits, 1 mongrel female rabbit and 9 mongrel female dogs by intravenous administration. In intravenous and intraperitonial administration animal death occurred only if the DF was given at high doses significantly greater than therapeutic ones: 6.0 g/kg, LD 50 5.0 g/kg for mice, 0.60 – 1.50 g/kg for rabbits, 0.51 – 0.90 g/kg for dogs. DF subchronic toxicity study showed the drug to be low toxic and well tolerable by the animals and neither had local irritation effect. As administered 0.1 - 0.2 ml 40 % FFs intra-tumorally (0.6 – 0.9 cm 3) to mice in inhomogeneous permanent magnetic field 0.2 T induction, 0.015 T/cm gradient FFs concentrated in tumor tissues and increase life span (ILS) of mice C57BL/6j with MX11 sarcoma to 130 % by site-specific induced hyperthermia of tumors at the frequency 0.88 MHz and peak field strength 9 kA/m. When administered intra-tumorally such fluids ILS of mice C57Bl/6j with implanted sabcutaneouslly Ehrlich carcinoma was to 120 %. When administered intra-peritonially such fluids do not increase life span of BDF 1 mice with implanted P388 ascitic leucosis.
SOME MECHANISMS OF ANTICANCER AND MODIFYING ACTIVITIES OF "INORGANIC" COBALT(III) COMPLEXES (AC-series)
Bubnovskaya L. 1, Levitin I. 2, , Sigan A. 2, Ganusevich I. 1
Michajlenko V. 1, Kovelskaya A. 1, Nechiporuk-Zlyj V. 1
1Inst.exp.Pathol.Oncol.Radiobiol.; Kiev, Ukraine
2Inst.Organoelement Compounds; Moscow , Russia
Objectives: to study the mechanisms of biological activities of "inorganic" cobalt(III) complexes with different biogenic ligands.
Materials&Methods: some "inorganic" cobalt(III) complexes that are containing no metal-carbon bond, were tested in vivo. Here they are exemplified by AC-30 complex. Transplanted rat tumor (Guerin carcinoma) was used in this study. Complex was given i.p. or i.v. Local hyperthermia (LHT) (1 h, 43 or 41 0C) was performed by microwave unit. The levels of glutathione (GSH) and malonyl dialdehyde (MDA), glutathione S-transferase (GST) activity in tumor and normal tissues and some indices of kidney and liver functions were determined by biochemical methods. Energy status in tumor and muscle was determined by 31P NMR spectroscopy.
Results: MDA concentration was increased by a factor of 3.5 in tumor to the 60 th min after AC-30 injection, in liver and kidney - 1.5 and 2, respectively. GSH content was decreased by a factor of 2 in tumor at the same time, in liver and kidney - by 10% and by a factor of 3, respectively. GST activity was decreased by a factor of 2 in tumor, in liver and kidney - by 10 and 20%, respectively. Decreased both MDA content and GST activity in tumor were kept unchanged within 24 h. All indices in normal tissues were reached the pretreatment values to the 24 h. AC-30 caused an drastic decrease in high-energy phosphates in tumor to the 2 nd h after injection. Tumor bioenergetic status has been reached the pretreatment level to the 24 th h. Kidney and liver functions were not significant disturbed due to AC-30 within 14 days.
Conclusion: it may be supposed that "inorganic" cobalt complexes exhibit anticancer and modifying effects by selective formation of free radicals in tumor (due to its hypoxia) which attack biomolecules and structures of cancer cells. Their influence on matrix proteinases can not be excluded.
SOME CHEMICAL CONSIDERATIONS ON THE TUMOR GENESIS STARTING
FROM ANALYTICAL DATA
*Campanella, L.; Giudiceandrea, F.; Pigliucci G.M.
*University of Rome LA SAPIENZA, Chemistry Department – Italy
University of RomeTOR VERGATA, Department of Surgery - Italy
The analytical determination performed in the environmental compartments (water, air, soil) show that some common polluttants are present at increasing concentrations. This is particularly true in case of heavy metals (Cd and Pb over all), hydrocarbons (expecially BTX), pesticides (meaningly organophosphoric and carbammic ones). Correspondingly always more numerous cases of tumours of liver and kidney are recorded so that possible correlations between the two phenomena can be investigated. The increasing concentration of organic polluttants in the environment can bring to their progressive accumulation in the target organs with formation of adducts to DNA and following cellular degeneration. The organism defends itself with metabolic and enzymatic activities finalised to consume these accumulated species. A study was performed on several cases (50<n<100) of cancerous and healthy kidneys and livers. So in the case of benzene metabolic capacity of kidney cancerous and healthy tissues due to the dioxigenase activity was measured. Higher values in the case of cancerous than healthy tissues were recorded so a defence mechanism activation being evidenced. Unfortunately the metabolic reaction produces metabolytes as muconaldheyde more toxic that benzene itself. To contrast this damage the introduction of a competitive agent of benzene toward dioxigenase, obviously characterised by non toxic or easily excreted by and final products, can be hypotized. This action can be probably enhanced by operating under heat, according to the parallel research performed by Roman University .
The conclusions are:
in cancerous organs cancerogenic environmental polluttants are accumulated.
to eliminate these accumulations it is necessary to adopt two different actions: firstly to add radical scavenger able to lower radicalic concentration and so their inhibiting action on the enzymes; secondly to prevalently enrich the oxidative enzymatic equipment of the singles especially if exposed to cancer risk.
REFERENCES
L. Campanella, G. Favero, M. Tomassetti
A modified amperometric electrode for the determination of free radicals.
Sensors and Actuators B 44; 559-565, 1997
Campanella L., Favero G., Mastrofini D., Tomassetti M.
Further developments in toxicity cell biosensors
Sensors and Actuators B 44; 279-285, 1997
Campanella L., Favero G., Tomassetti M.
A biosensor for determination of free radicals
In R. Puers (Ed.), Proceedings of Eurosensors X, The 10 th European Conference on solid-state trasnsducers, vol.3, Leuven 917-918, 1996
Campanella L., Favero G., Persi L.,Tomassetti M.
A superoxide dismutase biosensor to evidence the anti free-radical properties of healty and cancerous kidney tissues
SIB-BIB, Como , 28-30 april 1990
Campanella L., Favero G., Persi L.,Tomassetti M.
New sensors and biosensors for superoxide radical to evidence molecules of biomedical and pharmaceutical interest having scavengers properties.
8 th International Meeting on recent developments in pharmaceutical analysis, Rome 29 june-3 July 1999
HOMOGENEITY OPTIMIZATION OF TEMPERATURES AND DRUGS DURING PERITONEAL HYPERTHERMIC-ANTIBLATIC FOR PERITONEAL CARCINOMATOSIS
De Simone, M.; Nano, M.; Barone, R.; Izzo, G.; Cistaro, A; .Bacino, A.; Mattalia, P.; Aimone, M.; Cassolino, P.; .Camerano, R.; Villata, E; et Dei Poli M.
Università di Torino – Azienda Ospedaliera S.Giovanni; Torino, Italy
The peritoneal hyperthermic-antiblastic perfusion (HAPP) in partnership to the surgical cytoreduction seems one of the few weapons to disposition in the therapy of the peritoneal carcinomatosis. The presuppositions of such treatment are : 1) the presence of a peritoneal-plasmatic barrier, that allows to infuse great drugs concentration without systemic toxic effects ; 2) the synergic antineoplastic effect of e hyperthermia, with some drugs.
Varied groups of surgeons of the world have adopted two different types of HAPP : The "Closed Abdomen" one and the "Open Abdomen"one . The perfusion in closed abdomen is the fastest: at the end of the surgical cytoreduction, it foresees the closing of patient’s abdomen and than the perfusion of abdominal cavity is carried out through drains preventively set. The defect of this methodic is the dishomogeneity of drugs and temperature distribution. This is confirmed by no complete metilen blue diffusion introduced in the perfusion circuit (Sugarbaker). Aware of this limits many Authors have proposed some expedient : to shake the patient, to vary the inclination of the operating bed, to reverse the flow of the perfusion, to use very hot inflow temperatures (48°- 52°) (Gilly). Japanese authors have still proposed hot temperatures and fast flows (3 liters/min), which however are difficult to maintain in closed abdomen. Finally, a French author has proposed the use of 4 pumps and two heat exchanger, with low success.
To create an abdominal cavity, the perfusion in open abdomen foresees to suspend the skin of the incision to an "self retaining" retractor anchored on the operating bed and whose oval is set 10cms above the patient. The perfusion tubes are connected to a propulsion system made of two pumps, one for suction and one for feeding. These pumps are linked trough a reservoir that act as level regulator. During the whole perfusion the surgeon’s hand mix the solution in order to homogenize temperature and drugs.
The defect of this technique are the high thermodispersion and the risk of operating room contamination with drug , in case of leakage from abdominal cavity.
Materials and methods : due to the above mentioned reasons , in the last 27 patients we have tried to modify the "open abdomen" technique and to optimize the suction and feeding system. The partially closed abdominal cavity has been suspended to an self-reteining retractor , and we have called this method "partially closed" , leaving nevertheless an opening on the top which allow the introduction of the hand of the operator. This technique has allowed a lower thermodispersion , almost no contamination , better "hollow effect" , and a faster temperature uniformity. We have also worked to define the number and the dimensions of the hole in the inflow and outflow tubes. Actually we get quickly homogeneous intraperitoneal temperature using a system with 3 outflow tubes of 24F diameter ( under right and left diaphragm , pelvis) and 2 Y inflow tubes of 18F ( sovra e sotto mesocolico) . The 2 inflow tubes are the results of various experimental test to obtain Y branches with different lenght and holing in order to get the best diffusion of the solution.
Results and conclusions : starting from the partially closed perfusion use , the problem related to the contamination of the operating room are reduced , maintaining a good abdominal cavity edges perfusion and high flow (1,5 lt/min). In the last 12 cases with Y system and different length and holing , we have reached optimal and homogeneous temperature (42°C in the peritoneum) in a very short time and inflow temperature that are not over 44,5°C.
We think that the partially closed perfusion, as we performed, allows a good homogeneity of drug and temperatures with few problems of thermodispersion and contamination.
CYTOREDUCTION AND HYPERTHERMIC ANTIBLASTIC PERITONEAL PERFUSION IN RECURRENT OVARIANT CANCER AFTER 1 ST LINE OF CHEMOTHERAPY
M.De Simone, R.Barone, M.Nano, A.Bacino, E.Villata, M. Vaj , C.Franco, P. Cassolino, R.Camerano, A.Cistaro
Università di Torino – Azienda Ospedaliera S.Giovanni; Torino, Italy
The survival of patients with advanced ovarian carcinoma is 20% to 5 years. The middle survival at the moment of the recurrence after the first line of chemotheraphy ranged from 16 to 20 months. After surgical remove of a ovarian cancer at II or III stage, the recurrence is to load of peritoneum in 90% of cases. Initial studies regards the cytoreduction+chemo-hyperthermya in multi-recurrences ovarian carcinoma have given encouraging results, so that they stuffed us to propose a protocol of treatment in order to appraise the impact of the methodic on patients with first neoplastic recurrence intraperitoneal after chemotherapy. The protocol foresees also the execution of the lymphadenectomy, where it had not been already performed. A sistemic chemotherapy of consolidation within 5 weeks after intervention is provided.
Materials and methods :5 patients with intraperitoneal recurrence, appearance not before 3 months from the end of chemotherapy effected for primitive ovarian cancer, have been enlisted. They have been submitted to laparotomy with surgical cytoreduction, up to reach max tumoral dimensions, for every knot, of 1cm and to lymphadenectomy aorto-cavale and iliac-hypogastric. The hyperthermic-antiblastic intraperitoneal perfusion has been performed with 25 mg/l/mq of Cisplatino, in 4 liters solution, at temperature of 42°C on peritoneum, for 90mins. In all patiens the peritoneum illness was not particularly advanced (Peritoneal Cancer Index ranged from 1 to 10). The cytoreduction has been complete in all cases. In three cases the lymphadenectomy has been performed. In a case had been already done during the first surgical interventionOnly one patient has resulted N+.
Results and conclusions :Nobody of the treated patiens have had post-operating complications, neither local or systemic toxicity from Cisplatino except one case which suffered for a very long post-operative ileum. The therapeutic meaning of the lymphadenectomy is still uncertain and the literature data scarce still. Any complications due to the association lymphadenectomy+peritoneal perfusion, occured in our cases. In the other hand, once performed the pelvic pertonectomy, the lymphadenectomy aorto-cava-iliac-hypogastric is easy enough and it prolongs surgical time of c.ca 90-120 mins.
USE OF 99mTc MICROCOLLOID IN THE BLOOD LEAKAGE MONITORING DURING HYPERTHERMIC ISOLATED LIMB PERFUSION
M.De Simone, M.Baccega, P.Cesana, G.Izzo, M.Aimone Secat, R.Barone, A.Cistaro
Università di Torino – Azienda Ospedaliera S.Giovanni Torino, Italy
In order to avoid complications after isolated Hyperthermic limb perfusion several measurements methods of blood leakage are currently employed. Such methods may be affected by various problems due to stability of chemical binding of the compound in heparinate blood, low sensitivity and radiation protection normative.
99mTc- microcolloid (99mTcMC) was tested as a leakage indicator on a group of 32 patients undergone isolation perfusion for the treatment of malignant melanoma. 99mTc was preferred to Iodine to minimize radiation protection problems such as contamination of surgery tools, operating room and management of the patient.
99mTcMC was chosen for its high compound stability in the extracorporeal circulation
Our technique was already presented in ICHS Congress in 1997. Now we want to report results about method.
Pharmacokinetic studies confirm the high sensibility of the method. Pharmacological leakage is indeed less than 99Tc leakage and this means that our method is able to detect in real time minimal leakages. We considered the first 8 cases necessary for learning the method.
In the last 24 Isolated limb perfusions we change flow and the position of cannulae to achieve very low leakage rates. Only three times , for technical reasons, we couldnt have a leakage detected by Tc99 inferior to 15%.
As clinical confirmation we have had in the last 24 cases a very high rate of Histological Complete Response : 6 complete response in 8 Soft Tissue Sarcomas, and 8 in 16 in transit metastasis from melanoma. All the other 10 patients had histological responses of more than 70%.
In conclusion we believe that leakage measurement by Tc99 in Isolated Limb Perfusion is very effective, and can allow better clinical results in advanced neoplasms of extremities.
HYPERTHERMIA AND COLONY STIMULATING FACTORS.
Goliaei, B ; Jalal, R.; Khoei, S.; Minuchehr, Z.; Rajabi, H.Siamaki, K.; Soheili, Z.
The laboratory of Biophysics and Molecular Biology, Institute of Biochemistry and Biophysics, University of Tehran , Tehran , I.R.Iran.
Colony-stimulating factors (CSF) are hematopoietic growth factors which regulate differentiation and maturation of blood stem cells in normal physiological conditions. We have studied the effect of hyperthermia on the production of Granulocyte-Macrophage CSF (GM-CSF) by the lung tissue under various conditions. When mice lung tissue was minced into small pieces and heated in-vitro, there was a reduction in the production of GM-CSF in the heating range of 40-46 oC as judged by the colony formation assay in the soft agar tissue. The reduction was dose dependent. Under similar heat treatment, the total protein synthesis by the lung tissue showed a different pattern indicating a specific effect of hyperthermia on GM-CSF production as compared to most other proteins synthesized by the lung. Also, the activation energy of the two processes was found to be different. When the RNA from the heat-treated lung tissue was extracted and studied with slot blot analysis using a GM-CSF probe, it was observed that there was a specific reduction in GM-CSF gene expression in heat-treated lung tissue. In another group of experiments the chest area of rats was heat-treated in-vivo for one hr using a radio frequency heating device in the range of 38-41 oC. The animals were divided in two groups. The first group was sacrificed immediately after heat treatment and their lung was removed and assayed for the production GM-CSF. The second group was allowed to survive for various times after heat treatment to allow recovery from heat damage. The result showed that hyperthermia inhibited the production of GM-CSF within a few hrs after heat treatment, however; the animals could recover from this damage if they were given enough time after hyperthermic treatment. In conclusion, there are evidences that hyperthermia reduces the production of GM-CSF by the lung in a dose-dependent manner.
DEEP HYPERTHERMIA WITH SHORT WAVES OF PATIENTS WITH ADVANCED STAGE LUNG CANCER
Hager, E. D.; Krautgartner, I. , H.; Popa, C.; Höhmann, D.; Dziambor, H.
BioMed-Klinik Betriebs GmbH
Bad Bergzabern , Germany
Objective: Lung cancer is the leading cause of death from malignant disease in Western countries both in males and females. With respect to prognosis and therapy lung cancer is separated in small-cell (SCLC) and non-small-cell (NSCLC) subtypes. Approximately 75-80% of lung carcinomas are of NSCLC subtype, which includes adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Two thirds of all pts. with lung carcinoma will be diagnosed only at advanced stages of disease and are inoperable at the time of presentation because of either locally advanced disease or macroscopic dissemination. Surgical resection is the appropriate treatment of stage I, II and IIIa NSCLC, but at least 50% of these pts. will develop local relapse and/or distant metastases. The prognosis of pts. with advanced lung cancer is still poor, with a median survival not exceeding 8 months in large prospective studies of treated pts.. Long-term survivors (i.e., those who live more than 3 years) represent less than 5% of pts.. Polychemotherapy regimens reveal response rates (RR) of 25% to 40% among previously untreated pts. with NSCLC (<5% CR), and 60% to 90% among pts. with SCLC. The median time to progression is 3.7 to 4.2 months. New drugs are gemcitabine, vinorelbine, taxanes, irinotecan, and topotecan, which all have shown RR of 15% to 25% in previously untreated pts. Relapses indicate a very poor prognosis, depending from duration of relapse free time, because of high drug resistancy. Stage of disease, performance status and weight loss are definite predictors, including laboratory tests as lactate dehydrogenase and albumin. The poor outcome of chemo- and radiotherapy, especially after tumor relapse, and the treatment related toxicities are reasons for the search for new treatment modalities.
Patients and Methods: From 02/94 to 11/98 63 pts. with histological proven SCLC (n=10) and NSCLC (n=53) at far advanced stage of lung cancer have been treated with loco-regional deep hyperthermia (DHT) induced by radiofrequencies of 13.56 MHz (capacitive coupling). At onset of DHT all pts. were inoperable, refractory or at stage of relapse after prior surgery (30%), combination chemotherapy (46%), and radiotherapy (46%). Most of the pts. were at far advanced stage of disease (WHO/ECOG performance status 2: 36 %, 3: 29 %, and 4: 11 %). 86% of the pts. presented with restrictive disorder of pulmonary ventilation. An essential exclusion criterion was concommitant chemo- or radiotherapy. DHT treatment was started after local or distant progression of disease after primary conventional therapies (surgery, RTx, CHTx). 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 pts. were treated with palliative CHTx 8.4 and 28.5 months after onset of DHT due to systemic disease (e.g. pain).
Statistics: Prospective open single arm study with intention to treat analysis.
Results: The median overall survival time (MST) of all pts. was 14.0 months from 1st diagnosis of cancer. From relapse after surgery or 1st diagnosis of inoperable cancer the MST was 10.3 months. The MST from beginning of DHT was 4.7 months, with a median time interval between progress after conventional therapy to DHT of 3.2 months. The MST from progression after conventional therapy (surgery, CHTx, and RTx) was 9.5 months. The 1- and 2-year survival rates from progression of disease were 37% and 18%, respectively. DHT related toxicity was not observed.
Conclusions: DHT seems to retard tumor growth of pts. with lung cancer. From these data it can be concluded, that DHT with RF 13.56 alone may prolong survival time of pts. with lung cancer even at far advanced stages of disease after failure of primary conventional treatments. Quality of life could be improved or stabilized. An advantage of DHT in comparison to CHTx or RTX is that even it can be applied to pts. with poor performance status, hematological and cardial disorders and among elderly pts. - These results should be confirmed in randomised studies.
CLINICAL AND RESEARCH ASPECTS OF HYPERTHERMIA IN INDIA
Dr. Nagraj G. Huilgol and Dr. B. B. Singh
Indian Association of Hyperthermic Oncology and Medicine
Division of Radiation Oncology
Nanavati Hospital & Medical Research Centre,
Mumbai , India
The clinical use of hyperthermia in ancient system of traditional medicine (Ayurveda) in India has been known since 3000 B. C. It forms a part of an elaborate clinical protocol called "panchakarma" which is used for curative as well as preventive purposes. The protocol consists of vie purificatory steps following whole body or local hyperthermia.In recent times it has become extremely popular and forms a special subject of medical education in Ayurvedic colleges. There are three major aspect of this protocol which arouse great scientific curiosity; firstly, the fatty diet before hyperthermic exposures implicates the role of cellular membrane. Secondly, two hyperhermic exposures are always separated by ten to fifteen days to account for thermotolerance. Thirdly, hyperthermia is a prerequisite to all the steps in the protocol, the reasons for which are yet to be ascertained. Recent investigations on dietary facts on the hyperthermic response of transplanted solid tumours have indicated that high fat diet inhibitis tumour growth as well as development of thermotolerance. Mild whole body hyperthermia has been demonstrated to enhance immunological competence in animals. Implication of these observations will be discussed.
SECOND GENERATION ULTRASOUND ARRAYS FOR
THERMAL THERAPY IN BREAST CANCER
Johnston, R., Ph. D.; Blight, D.; Kouzmanoff, J., MSEE
Labthermics Technologies, Inc.
Champaign , Illinois , USA
There are distinct advantages in using ultrasound energy to heat breast tissues. As can be seen on diagnostic ultrasound scans of the breast, ultrasound energy is preferentially absorbed by tumor tissue components and to a lesser extent by normal tissues. This is due in part to higher collagen and protein content in tumors. In contrast, microwave energy produces higher temperatures in high resistance tissue, such as fat, and less heating in more electrically conductive tissues, including tumor. An additional advantage of ultrasound is a selectable depth-dose" of the heating beam. By changing frequency of the ultrasound energy, we can chose a heating profile that matches depth and thickness of the tumor.
A new ultrasound therapy system has been built that maximizes the therapeutic benefits of ultrasound. The system uses 16 wedge shaped transducer elements to match variable geometries of breasts and tumor locations. These elements can be driven at multiple simultaneous ultrasound frequencies to yield a truly three-dimensional heating beam. Ultrasound energy is directed tangentially to the chest wall in order to minimize heating of ribs or intercostal muscles.
In use, the patient lies on her side with the breast over a water-filled pillow on top of the treatment array. An attached ultrasound diagnostic scanner images the breast from above. A computer stores the scans and builds a three-dimensional image of the treatment area, tumor locations, and temperature sensor locations. This information is given to the treatment-planning program. The therapy array is then electronically customized for the treatment plan. Additional diagnostic ultrasound scans can be taken during therapy to insure correct registration of patient position.
The system is presently in clinical animal trials at the University of Illinois . Applications to the FDA for human use will be made soon. The system has been designed to function as a stand-alone therapy unit or as configurable modules for the present SONOTHERM Ultrasound Hyperthermia System.
This work was funded in part by National Cancer Institute Grant CA65206
COMBINED MODALITY LOW DOSE CHEMOTHERAPY AND THERMORADIOTHERAPY:
A NOVEL TREATMENT APPROACH FOR LOCALLY ADVANCED UNRESECTABLE PANCREATIC CARCINOMA
Kawana, A.,M. D.; Quasabian, L., M. D.; Bicher, H., M. D.
Surgery Hematology Oncology Medical Association;
Los Angeles , California , USA
Valley Cancer institute; Los Angeles , California , USA
Abstract: Case Study
Despite recent advances in the treatment and diagnosis of locoregional pancreatic carcinoma only 10 too 15% of cases are amenable to resection. Unresectable tumors are often complicated by pain, anorexia, weight loss and fatigue. This case study explores the use of palliative combined thermoradiotherapy with low dose 5-fluorouracil. The patient is a 75 year old male with a two month history of severe abdominal pain and bloating. CT scan of the abdomen revealed a 4.5x3.6cm. mass in the pancreas encasing the splenic artery. CT guided needle aspiration revealed adenocarcinoma. Initial CEA was 3.7ng.ml and CA 19-9 was 108 u/ml with a pain scale of 10 of 10 despite narcotic analgesics. The patient began treatment with hyperthermia and low dose radiation to the pancreas and leucovorin 100mg. IVP weekly with 5-fluorouracil 1500mg. by continuous IV infusion (800mg/m2) over seven days. The patient experienced almost immediate pain reduction to 5 of 10 after the first day of hyperthermia. The patient’s tumor markers inexplicably rose two weeks after the initiation of treatment to CA 19-9 of 161u/ml and a CEA of 4.29 ng/ml. One month after ignition of therapy the patient was pain free off narcotics and had no symptoms of anorexia or fatigue. After six months of therapy the patients CA 19-9 had decreased to 56 u/ml and CEA to 2.9 ng/ml. Unfortunately, by the seventh months of therapy the patients tumor markers began to rise although the patient remained assymptomatic (CA 19-9 or 82). Finally, during the eighth month of therapy the patient’s pain returned and therapy was discontinued.
Conclusion:
Combination thermoradiotherapy with low dose continuous 5-fluououracil and leucovorin is a well tolerate modality which may provide significant palliation in patients with unresectable pancreatic carcinomas and deserves further study.
BIOCHEMICAL AND HEMATOLOGICAL CHANGES
OF CANCER PATIENTS AFTER WBH
Kurpeshev, O.; Pavlov, V.; Smirnova, I.
Medical Radiologicai Research Centre; Rams, Russia
Twenty patients with disseminated tumors ( mal-ignant limphoma, breast carcinoma, lung cancer and melanoma ) were given WBH ("Yakhta-5", 13,56 MHz). Each patient received 1 to 4 WBH procedures with the breacs from 2 weeks to 6 months. Totaly 32 WBH procedures were performed. Temperatures were measured on tympanic membrane, in esophagus and in the rectum. The main criterion for assesment of hea-ting level of patients was the rectal temperature, that was in the range of 41,3-42,3oC ("plato phase" ) with duration of 60-100 min. All the patients (but one) WBH was combined with chemotherapy. Moråover, all the patients received detoxication treatments. After WBH we’ve seen a decrease in all blood indices was noted. Those changes occured earlier and were more marked compared to chemotherapy only. The level of some biochemical findings of some patients increased till 1,5-2 times. Only concentration of blood serum myoglobin increased up 10 times. More intensive changes had the patients wich received more strong regime WBH (42,3îÑ/60 or 41,8îÑ/100 min. ).
CAVITATION - IS IT POSSIBLE AFTER HYPERTERMO-
RADIOTHERAPY IN THE MUCOSITIS?
Ljubenov, T.
Clinical Centre of Nuclear Medicine and Radiotherapy -
Med. University Sofia , Bulgaria
When the radiolysis of the extra- and intra-cellular fluid begins and other chemical reactions, with the thermoradiobiological processes, then are formed the so-called cavitation under the mucous membrane in the oral cavity. Cavitation (small bubbles) is a violated homogeneity of a fluid as a result of the hydrodynamical change after local hyperthermia and radiotherapy, in which the pressure reaches a critical value of decrease and the number of the bubbles, full of gas or vapor, grows unlimitedly. In vivo measurement show the importance of the obtained specific absorption rate (SAR in mW/g) for the temperature elevation dT. Therefore, by further increasing heating for this specific SAR selection, an overheating of mucosa (often near the tumor because of too strong focusing) is treatment limiting. For characteristics of such small bubble we introduce the parameters p 0 (the pressure in it), r (the radius of the bubble) and p (the density of the which is found in the bubble). The conditions necessary for appearance of a destructive trace of the bubble (so-called cavitational erosion or ulceration in the epithelium) are:
semispherical form and adhesive to the mucosa,
b) the bubble is far away from the mucosa, etc. The time (T) and the velocity (v) of the embryonic formation of the bubbles we can denote with formula:
T= (P/P o) ½ . r or V=r/T=(P/P o) ½
THE BIRTH AND DEATH OF A HYPERTHERMANOLOGIST
McLaren, J., M.D.
Emery University Medical School
NCI conference and proceedings circa 1978
Leveen’s article in JAMA-c 1979
Bicher’s article in Yellow Journal –circa 1979
Holt’s publication of 40+ patients treated with cobalt 60 alone, +HBO, +HEAT
a) Hornbach’s – visit
b) Caldwell ’s –visit
Caldwell ’s TIE-IT-TOGETHER conference at the
University of Wisconsin in Madison
My visit to Leveen’s and Hornbach’s-Shidia’s facilities
Bicher’s first NAGH meeting in Detroit
Hornbach’s and Mclaren’s formation of a clinical
society- ICHS
Emory’s adventures into hypothermia with capacitance
and 434 MHz units with good physics support
The Harris company, BSD, Clinitherm, etc.
11. Emory’s purchase of Clinitherm Unit- primary for BPH
12. Concern of HSP’S –potential of HSP
FDA rules only reimbursement for heating superficial
lesions + radiation
The number of units in Atlanta drops from 6 to 0 which mirrors USA
Continued work off-shore of USA has kept hopes alive Possibly younger and brighter minds during the new millennium can put the physics and biological proven benefits of heat to clinical advantage!!!
MICROWAVE BALLOON CATHETERS FOR TREATING BPH
Mendecki, J.; Meiman, A.; Rechtescaffen, T. – Dept. of Urology Montefiore Medical Center , Bronx , New York , USA
Sterzer, F.; Mawhinney, D.; – MMTC; Princetoon , New Jersey , USA
F. Cheung, J. Mon – Celsion Corp.; Columbia , Maryland , USA
We have developed instrumentation which combines microwave heating with balloon dilatation to produce a biological stent in the urethra. This approach is designed to safely and effectively treat patients with BPH in a single session without anesthesia.
The basic innovation of this procedure is the use of modified Foley catheter which in addition to the anchoring balloon is equipped with a compression balloon at the level of its intraprostatic segment. The distention of this balloon is accomplished by means of circulating deionized water under pressure, which also provides cooling of the urethra during administration of hyperthermia.
During Phase 1 of the program, animal trials were performed on 11 dogs in whom thermocouples implanted directly into the prostate serviced to determine temperature levels necessary to produce dilatation of the prostatic urethra. With rectal and urethral temperature monitoring to maintain the safety range, an algorithm of temperature/power parameters needed for a safe and effective procedure has been established. Also a novel microwave radiometer for non-invasively monitoring subsurface tissue temp. during the microwave heating will be described. The method has now been tested successfully on 10 patients with BPH. Results of animal and clinical trials will be presented and discussed.
PORATION OF MALIGNANT TUMORS WITH MICROWAVE PULSES
Sterzer, F.; Mendecki, J.*, Friedenthal, E. #; Mawhinney, D.;
Meiman, A. *,
MMTC Inc. Princetoon , New Jersey , * Depart. Of
Urology, Albert Einstein College of Medicine, Bronx , New York , USA
# Rad. Oncol. Calvary Hospital Bronx , New York , USA
Electroporation is a process by which cell membranes are temporarily made more permeable by application of dc pulses to the tissue. One of the main sues of dc electroporation is to enhance the uptake by the targeted malignant cells of chemotherapeutic agents, particularly those with large molecules which normally are not able to penetrate the cellular membranes. Because dc poration techniques require contacting or implanted electrodes, the process is usually limited to the treatment of superficial tumors.
We have developed a non-invasive, clinically-usable method of microwave poration which permits to directly beam high peak power microwave pulses into target tissue. Our experiments were designed to assess the efficacy of the pulsed microwave signals in achieving in tumors poration effects equivalent to those produced to dc fields without the use of electrodes, thus allowing for non-invasive treatment of deep as well as superficial tumors. In a study on rats implanted with malignant prostate tumors we were able to demonstrate that the uptake of systemically administered high molecular weight fluorescein dextran (10,000D) was significantly and selectively increased by microwave pulsing of the tumors. A preferential uptake of such molecules by malignant tissue as compared with healthy tissue was also demonstrated.
THE COMBINATION OF CHEMOTHERAPY AND HIGH FREQUENCY HYPERTHERMIA IN GALL BLADDER CANCER
Migeod, F., M.D.; Douwes, F., M.D.
Klinik St Georg, Rosenheimerstr; Bad Aibling , Germany
46 patients (22 male, 24 female) with inoperable (n=39) or recurring (n=7) cancer of the gall bladder, bile duct or cholangiocellulary carcinoma were treated with a combined thermo-chemotherapy between September 1994 and January 1998. A local tumour as single location was found in 26/46 patients, additional metastases in 20/46 patients i.e. liver (n=16), peritoneum (n=11), lung (n=3), other (n=7). Patients with brain metastases were excluded. Median age was 63,3 years. All patients with gall bladder carcinoma had a history of gall bladder stones or resection. At the beginning of the treatment, 39/46 patients (85%) were taking analgesics i.e. opoids, NSAR. Chemotherapy included Mitomycin C, 8mg/m² day 1 & 3, folinate acid 200mg/m² i.v. day 1-5, & 5-FU 500mg/m² i.v. 2 hrs/day 1-5/4w, simultaneously with high frequency (13,56MHz) hyperthermia day 1, 3, 5, 8 & 10 (Oncotherm EHY system). In total 185 treatments regimes with 925 HF-hyperthermia were administered in the period mentioned above.
Sufficient temperatures were attained in 84,2% of all treatments carried out. Side effects for example, increase in pain during hyperthermia (9,3%), gastric symptoms (8,2%), fat tissue granuloma (4,3%) were observed. Thrombopenia occurred in all patients, n/e in 7/46 patients. Stomatitis in 10/46 patients and diarrhoea in 18/46 patients, WHO grade II / III. Pain reduction was observed in most patients (32/39), thus a reduction in analgesics quantity. CEA sensitivity in 25/46 patients, CA19-9 in 20/46 patients and a decrease in over 28 cases was observed. 70% objective responses in the primary or recurring sites (CT or NMR) were; 1/46 (CR), 17/46 (PR), 14/46 (MR/NC), progression in 14/46 patients (30%). The responders (CR + PR) time till progression was 11,2 months and survival 28,4+ months. In non-responders (PD), mostly those with metastased disease only 6,2 months was attained. The non-responding metastasing disease had a worse survival rate (6.2 months) than the non-responding local disease (9.0 months).
In conclusion, the hyperthermic effect is not only attained by heating, e.g. hypoxia and acidosis, but also by increasing intra-tumoural cytostatic effects and enhancing the immunological cytokine effects. The treatment is practical and tolerable, causing an encouraging rate of remissions and pain reduction, with minor complications.
THE EFFECTS OF HIGH FREQUENCY HYPERTHERMIA & COMBINED THERMO-CHEMOTHERAPY IN PLEURAL EFFUSIONS & ASCITES.
Migeod, F., M.D.,
Klinik St Georg, Rosenheimerstr; Bad Aibling , Germany
Pleural & pericardial effusions and ascites are often found in malignant diseases, especially in lung cancer, malignant lymphomas, mammarian cancer, acute leukemias, gynological & gastro-enterological tumors as gastric cancer. 40% of all pleural effusions, 20% of all pericardial effusions are of malignant origin, as well as 70% of all ascites. Commonly, effusions occur with a specific weight of <1016, protein over 30g/l.
The effect of a high frequency hyperthermia was investigated with regard to effusions with malignant cytology (Oncocare machine, Bruker system, 13,56MHz, 60 min., temperature over 21 ° C). Further investigations were carried out using a combined thermo-chemotherapy with the application of a mono-chemotherapy in to the effusion. The temperature was measured within the effusion by means of a fibre-optic system.
Reactions to therm-chemotherapy were seen in cases of gastric cancer, ovarian cancer, mammarian cancer and hypernephroma. The destructive effect from different hyperthermia temperatures was confirmed. We noticed an increased efficiency in cases where adjacent immune cells were found, especially in the dendritic type of myelomonocytic cell row (CD34). The dendritic reticulum cells play an important role in the processing and presentation of antigens to T-Cells. Pluripotent CD34 stem cells were collected by plasmapheresis (cell separator AS104, Fresenius Co.) These were taken to an ultra-violet photopheresis and reinstillated in the effusion to elevate cytotoxic activity.
THE COMBINATION OF CHEMOTHERAPY AND HIGH FREQUENCY HYPERTHERMIA IN PANCREATIC CANCER
Migeod, F., M.D.; Douwes, F., M.D.
Klinik St Georg, Rosenheimerstr; Bad Aibling , Germany
46 patients (27 male, 29 female) with inoperable (n=46) or recurring pancreatic cancer (n=9) were treated with a combined thermo-chemotherapy. Local tumour as single location was found in 26/46 patients, additional metastases for example, liver (n=19), peritoneum (n=20), lung (n=9), other (n=5), brain metastases were excluded from the study. Median age was 59.2 years. 73% of all patients were taking analgesics at the start of the treatment programme. Chemotherapy included Mitomycin C (8mg/m² day 1 & 3), folinate acid (200mg/m² i.v. day 1-5), & 5-FU (500mg/m² i.v. 2 hrs/day) simultaneously with high frequency (13,56MHz) hyperthermia days 1, 3, 5, 8 & 10 (Oncotherm EHY system, Germany ) to the pancreas area. In total, 193 treatments regimes with 965 HF-Hyperthermias were administered between October 1993 and December 1996. Temperature control was achieved by duodenal probes. Sufficient temperatures were attained in 80.3% of all treatments carried out (42.1 - 44.0, median 42.5C). Side effects for example, increase in pain during hyperthermia (9.2%), gastric symptoms (12.4%), fat tissue granuloma (1.3%) were observed during the course of the treatment programme. Thrombpenia occurred in all patients, N/E in 8/46 patients, stomatitis in 10/46 patients and diarrhoea in 21/46 patients. Pain reduction was seen in patients with tumour pain, allowing for a reduction in analgesics quantity. CA19-9 sensitivity was attained in 41/46 patients. Objective responses in the primary and recurring sites (CT + NMR) were as follows: 1/46 patients (CR), 16/46 (PR), 22/46 patients (NC), 7/46 patients (PD). In time till progression (CR+PR) a period of 8.5 months and a survival of 16.1 months was observed in comparison to non-responders (PD) only 6.7 months. The non-responding metastased disease showed a worse survival rate (4.2 months) than local disease (9.0 months)
In conclusion, the hyperthermic effect is not only attained by heating, e.g. hypoxia and acidosis, but also by increasing intra-tumoural cytostatic effects and enhancing the immunological cytokine effects. The treatment is practical and tolerable, causing an encouraging rate of remissions and pain reduction, with minor complications.
INTERSTITIAL HYPERTHERMIA AND PAIN CONTROL
Mykhalkin, I. , M. D., Ph. D.
National Analytical Center, Medium, Institute of Experimental Pathology
Oncology and Radiobilogy Problems, Kiev , Ukraine
The treatment in clinics more than 200 patients established the regime based on pain feelings of the patient. The regime of control was decided for the following reasons:
1. Technical complexity of the installation of thermo-couples into the tumors.
2. Pain and psychotrauma of the thermo-couples installation procedure for the patient.
3. Less informative efficiency of thermo-monitoring after 2-3 procedures of hyperthermia with temperature measurement. Considerably frequent cases when thermo-couples are inserted into tumors presents a complicated operation (tumor of stomach, trachea). Necessity of temperature control with the regular tumor size control and big quantity of hyperthermia sets quite problematical. Pain feelings of patient is he isn’t scared of the procedure will determine efficacy of heating.
During the treatment of the malignant tumor, located up to 4 cm. under the skin experienced on dogs, heating was used by means of two tows of needles. The needles were inserted into the bottom and the top of the tumor. A distance between the needles is not more than 1 cm. in each row. The needles were supplied with a voltage of 1,73 Mhz frequency. The temperature was controlled in the center of the tumor and was kept during 60 min. on the level of 42-44C. In the area of the inserted needles it reached 50C. The dog was kept under narcoses. Applied technology allowed (due to high thermal dose) to kill the most livid and best blood supplied tumor ar4eas. After the first set of hyperthermia a regressivity of 50% was observed. 3 sets were sufficient for the total regressivity of the tumor for 5 dogs from each 9.
ALFA-INTEFERON AND CONTRICAL AS AN ADJUVANTS FOR HEAD
AND NECK CANCER THERMORADIOTHERAPY
Mykhalkin, I. , M. D., Ph.D.; Bykow, V., M. D., Ph. D., Sc.D.;
Iashvilli, Z., M. D., Ph. D.
National Analytical Center, Medium Oncology Department of Institute of Otolaryngology, Kiev , Ukraine .
One hundred forty two patients with primary head and neck cancer were treated. Local microwave hyperthermia was achieved by electomagnetic field at 915 MHz with 0.5 to 0.6 W/cm square power density for the external heating technique and at 2450 MHz with 7 to 8 W/cm square power density for the intracavitary technique.
The local hyperthermia essentially increased the complete response of head and neck cancer. The using of inhibitor of proteolysis and interferon alone or together did not have influence on short-term reception.
The hyperthermia increased compared with radiation therapy alone by about 21%. No response in all groups with hyperthermia and adjuvant therapy hesitate about 14% and was not more than half of the data at group with radiation therapy alone. Our clinical investigations with inhibitor of proteolysis-contrical confirmed these data. Finally, the ajuvant therapy perhaps will play an important role in the primary radical treatment of cancer patients.
"Magnetron" from 1996 year used for treating of deep (200mm) located malignant tumors of brain, ovarian and intestinum, as report chef of Kyivs City Oncology Center’s Radiology Department. Result observed after second hyperthermia seance and bleeding stoppage of gynaecology organs tumors.
HYPERTHERMIA IN COMBINED TREATMENT OF HUMAN TUMORS
I. Mykhalkin M. D., Ph.D.; A. Gussev, Ph. D.; Yu. Medinets;
A. Mylianovskiy M. D., Ph.D., Sc. D.; V. Protsyk M. D., Ph.D.,Sc.D.;
V. Cherny M. D., Ph.D., Sc.D.
National Analytical Center, Kyiv City Oncology Center, Kyiv Medical Institute; Kiev , Ukraine
234 Patient with different tumor localizations have been treated combined with thermoradio- and chemotherapy. Tumor sites were as follows: rectum cancer 45, head and neck tumors 59, preinvasive cancer of the cervix with cervical neoplasia lesions 130. hyperthermia was administered using a microwave unit operating at 915 MHz power density 0.9-10 W/sq.m and 27.12 power density 0.3-10 W/sq. m (43C, 1h. after radiation). Hyperthermia was commenced within 1 an 1.5 h after the radiation. Antitumor drugs were given by infusion. Remission duration was enhanced by an average from 6 to 12 months, two years survival increased two-fold, three years 2-2.5 fold, five years 1.5-fold. The number of complications due to treatment use were not increased significantly, combined therapy was observed. The problems of hyperthermia application in combined treatment of oncologic patients are under investigation.
In some cases we used the rectal and vaginal changed applicators with condom. Magnetic hyperthermia irradiancer located in especial plastics stool. Irradiancer includes 1) Lamps ry-48 200 W (2ex), ry-49 (4 ex), ry-72 (4 ex) 2) transistor KT944A (4ex) KT956A, KT95\64A, KT980A, TT9126A, TT9131A,3) field-effect transistors KT1904A (4ex) KTI913A (4ex) 4) digital display AJIC331A (2ex) 3JIC345A (2ex) HB-nilJ 1-8113 5) printed thir-film microcircuit K176 (4ex) 6) capasitor K-50-35 (8ex), 7) cable PK-50-9-23 (10 feet) *) fiber-optical temperature measurement.
First step for one of best way for saving hyperthermia, our opinion, is producing a few thousand of cheap small hyperthermia irradience apparatus for every sweet home in USA, united European states, Australia, United Arabic Emirates, etc. (not for Canned, Ukraine, Russia etc. states with government medical care system) and giving possibility to say and work for progressive non-conservative scientists.
THERMOREGULATORY MECHANISM IN THE MALIGNANT CARCINOMA TREATMENT BY ELECTROMAGNETIC HYPERTHERMIA COMBINED WITH RADIOCHEMOTHERAPY
Mykhalkin, I. , M. D., Ph. D.
National Analytical Center Medium, Institute of Oncology ; Kiev , Ukraine
Electromagnetic hyperthermia with radiation therapy and chemotherapy were carried out in 165 patients with malignant tumors. Analogous experimental investigations were accomplished on mice, rats and dogs. Rehabilitation of patients was accelerated, rate of irradiation reaction was dimensioned and terms of treatment of the patients were shortened. In addition the delay of transplanted tumors growth and the increasing of lifetime of animals were achieved. Various methods of electromagnetic hyperthermia make quite different structures of heat productions of heterogeneous tissue. Microwave heating supplies the zone of effective heat production in muscular tissue as deep as 2-4cm., with maximum of the heat production on the surface of skin.
Usage of strong heating makes the patients to feel pain. Application of coolers are widely used in electromagnetic hyperthermia. The heat receptors do not react with pain. Our cancer patients sensed some discomfort, the feeling of pressure in the tissue or could not express their feeling under electromagnetic hyperthermia.
The temperature in the tumor may go as high as 47 degree Celsius. The muscular tissue temperature goes up to 41-43 degree Celsius because of intensive blood circulation. The use of in inductive heating with the help of changing magnetic field gives the maximum heating influence to the tissue obtaining much liquid. That’s why the implementation of the inductive method is very effective in case of the tumors of soft tissue. Together with the mediLAK Company we worked out inductive irradiators with low level of heating. They undergo some approbation in oncological and orthopedy clinics in Kyiv and analongs of our irradiators from 1993 in Japan . Such irradiators are especially effective when used to treat different inflammation diseases.
HYPERTHERMIA TREATMENT OF INFLAMMATORING DISEASE
Mykhalkin, I. , M. D., Ph.D.
National Analytical Center, Medium; Kiev , Ukraine
At present the application in oncology of electromagnetic hyperthermia with the aim of treat of different tumors is being widely spread. Using electromagnetic hyperthermia in heat production takes place in tissue volume, while they are oriented on heat transmission. That was the reason of our investigation of thermoregulatory reaction of tissue after using electromagnetic hyperthermia. In radio-frequent capacitive heating the spread of heating depends on the ingredients and configuration of the heating tissue. The bone and fat tissue are being mostly heated under such type of heating. The thermoregulatoring system in the bone tissue is absent, the fat layer plays the thermoregulating in the body. That’s why in treating the bones sarcoma this method is rather effective.
Our experience in application of radiofrequency irradiators showed high efficiency for treatment of inflammatory disease of throat, lungs, woman genitals, chronical sinusitis. Application of liver heating showed a high efficiency for improvement of its function in the rehabilitative period after hepatitis.
The average temperature is calculated taking in to account time of being applied. The highest thermoproduction is usually concentrated in the area nearest to the radiator of the tumor. The temperature inside of the tumor during the hyperthermia is quire irregular. The temperature of the difference points of the tumor can be defined also by the velocity of the heat flow of the bloodstream. That is why in the narcotized point of the tumor the temperature is higher than in others. The lower temperature appears in the farthest point of the tumor with high blood stream intensity, the low level of thermoproduction appears in this area as well.
Therefore, in our opinion, on the thermal dose chart, the tumor should be divided into several areas. The most intensive monitoring should be done in the less heated areas. The less intensive monitoring should be done in the necrosis area. Thermal dose should be calculated separately for every point. An averaging of the thermal dose, on our opinion, will only distort the real picture of the heat action efficiency.
OVERVIEW OF HYPERTHERMIA PHYSICS
Gilbert H. Nussbaum, Ph.D.; Mallinckrodt Institute of Radiology
Washington University School of Medicine
St. Louis , Missouri , USA
While the biological and physiological rationale for utilizing hyperthermia in the treatment of cancer is sound, the administration of satisfactory thermotherapy is often quite challenging. The induction and maintenance of clinically prescribed temperature elevation in targeted tissue requires that the methods employed for deposition of power and determination of temperature in-vivo be appropriate to the treatments given. This overview will identify and briefly discuss the factors governing tissue heating, i.e., energy balance, bioheat equation, specific absorption rate and perfusion rate. Characteristics of power deposition by microwaves, ultrasound and rf electric currents will be summarized. Techniques and clinical applications of interstitial hyperthermia will be discussed, as will performance characteristics of various heating applicators and thermometers.
"INORGANIC" COBALT(III) COMPLEXES WITH TETRADENTATE SCHIFF BASES AND BIOGENIC NITROUS BASES AS A NEW ANTICANCER AGENTS WITH RADIO/THERMOSENSITIZING ACTIVITIES
Osinsky S. 1, Levitin I. 2, Bubnovskaya L. 1,Sigan A. 2,Ganusevich I. 1
1 Inst. exp. Pathol. Oncol. Radiobiol.; Kiev- , Ukraine
2Inst. Organoelement Compounds; Moscow , Russia
Objectives: to test the biological activity of "inorganic" cobalt(III) complexes with tetradentate Schiff bases and different biogenic nitrous bases or an analogous synthetic ligands.
Materials & Methods: some cobalt(III) complexes with basic structure [ Co(acac 2en)(NH 3) 2 ] Cl that are containing no metal-carbon bond, and their analogs with different ligands were tested in vivo. Here they are exemplified by AC-11, AC-30 and AC-40 complexes. Transplanted rodent tumors [ Guerin carcinoma, Walker-256 carcinoma, Lewis lung carcinoma (3LL), melanoma B16, adenocarcinoma Ca755 ] were used in this study. Complexes were given i.p. or i.v.. Local hyperthermia (LHT) (1 h, 43 or 41 0C) was performed by microwave unit. The tumors were irradiated by 190 kV X-rays at 1.23 Gy/min (RT). Tumor ¢ s response to treatment was estimated by standard methods.
Results: all cobalt complexes of AC-series have been shown to display substantial anticancer, in particular antimetastatic activity: 1) primary tumor inhibition: Guerin carcinoma by 72 (AC-11), 74 (AC-40) and 74% (AC-30), Ca755 - by 76 (AC-11), 77 (AC-40) and 79% (AC-30); B-16 – by 50 (AC-11), 57 (AC-40) and 65% (AC-30); 2) metastases inhibition: 3LL – by 67 (metastases number) and 90% (metastases volume) (AC-11) and 84 and 99% (AC-30); B16 – by 75 and 76% (AC-11) and 71 and 99% (AC-30). Moreover, these complexes have enhanced the antitumor effect of LHT (Tumor Growth Delay after "41 0C+AC" was the same with those after 43 0C alone) as well as RT (dose modifying factor = 2.0). Some other analogs of above mentioned complexes with other biogenic bases are under design and investigation.
Conclusion: our results have indicated that "inorganic" cobalt complexes can be regarded as prospective selective anticancer agents with significant modifying activity.
TWENTY YEARS EXPERIENCE IN LOCAL MICROWAVE HYPERTHERMIA COMBINED WITH RADIO- AND/OR CHEMOTHERAPY IN UKRAINE
Osinsky S. 1, Protsyk V. 2
1Inst. exp. Pathol. Oncol. Radiobiol., Kiev , Ukraine
2Ukr. Res. Inst. Oncol. Radiol., Kiev , Ukraine
Objectives: to estimate the efficacy of local hyperthermia (LHT) and induced hyperglycemia (IHG) in the combined treatment of some malignant tumors, in particular head and neck cancer (HNC).
Introduction: 5 center use LHT in the combined treatment of human tumors in Ukraine . More than 780 patients have been treated by microwave LHT till 1999. "Thermotron-RF-8" was begun to apply in combined cancer therapy since 1997. 274 patients with HNC (T 3-4N 1-2M 0) there are our own experience.
Materials & Methods: LHT was administered using a microwave unit (Istok Ltd., Russia ) operating at 915 MHz (43 0C, 1h). IHG was commenced 1 h after radiation (RT), LHT – within 15-25 min after IHG. Antitumor drugs (CHT) were given simultaneously with IHG. It was used the infusion of a 20% glucose solution into vessels feeding the tumor at a rate of 15-20 mg/kg per min over 45-60 min (glycemia level=10-12 mM; tumor acidification was confirmed by biochemical determination of lactate in tumor).
Results: Application of LHT in combination with RT and/or CHT supplemented with IHG has allowed to receive the following results: systemic toxicity of CHT or the acute RT response of normal tissues were not increased; number of tumor complete regression was increased by 30-45%, time to recurrence - by 5-7 months, the 3-year survival – by 15%, 5-year – by 8-10%, the index of operability – by a factor of two. Some problems with temperature measurements were observed, in particular under fractionated heating.
Conclusion: LHT has significantly enhanced both RT and CHT effects. IHG using has positive influenced on LHT and/or RT and CHT antitumor effect. Special balloon-catheter and embolization of vessels feeding the tumor with new substance "Emboline" (Shcheglov V. et al.,1998) are proposed (Osinky S., Shcheglov V., 1999) to overcome inhomogenous heating of tumor.
ABLATION OF LIVER TUMORS WITH
RADIO FREQUENCY NEEDLE
Page,R., M.D., F.A.C.S., F.S.S.O.
Page Clinic, Mid South Surgical Oncology Center
Memphis , Tennessee , USA
An exciting procedure has been developed utilizing a novel ablative technique to treat liver tumors with radiofrequency interstitial tumor ablation device or R.I.T.A.
Spread of cancer to the liver can be a very ominous finding. Until recently surgical removal of a major portion of the liver was the only option, and this can be a very serious procedure, often associated with complications. Now, with ultrasound guidance, we can destroy the tumor with a radiofrequency energy. This is accomplished with a recently developed high tech very special needle, that can be inserted into the tumor very accurately guided by ultrasound, at which point four fingers can be deployed allowing for destruction of a 3.5cm mass in seven minutes with temperatures of 90-100 c achieved. If the tumor is larger then multiple applications will be required. This can be accomplished via the transcutaneous route or by utilizing the laparoscope, allowing direct visualization of the liver and more accurate placement of the needle ablating device.
The technique, results and complications will be discussed.
POTENTIAL EFFECTS OF HYPERTHERMIA ON ENZYMATIC ACTION IN CANCER THERAPY
Pigliucci. G.M.; *Ercole P.; *Campanella. L.
University of RomeTOR VERGATA, Department of Surgery ; Italy
* University of Rome LA SAPIENZA, Chemistry Department ; Italy
Many Authors have demonstrated the therapeutic effects of hyperthermia in cancer treatment. Particularly, microwave or radiofrequency hyperthermia (41.5- 42.0 C°) increase the effects of other traditional approaches such radio and chemotherapy with an elective action on neoplastic cells avoiding relevant side effects on healthy tissues.
Our study has underlined the relationship between some experimental results and the more accredited theories about the action of heat on tumoral cells (sensitivity increased by the hypoxic methabolism of tumoral cell and the induction of a stop in DNA replication). Heat seems enhance some enzymatic mechanism that neutralise cancerogenic environmental pollutants accumulated in neoplastic cells like Benzene. This results could suggest a possible role for enzymatic defect in the origin of malignancies. The defect could be congenital or acquired for functional modification produced by different causes, included infectious disease.
This hypothesis, that undoubtedly needs of more experimental and clinical confirmations above all about the different tumoral hystotype, suggest a new way in cancer treatment based on enzymatic activity modulation.
In this context, hyperthermia can play a significant role as an easy and safe modulating agent.
REFERENCES
1) R. Fiorito, G.M. Pigliucci, D. Venditti, B. Iorio,F. Giudiceandrea, V. Cervelli, V. Vittorini, C.U. Casciani.
Efficacy of hyperglycemia to increase the effects of radiotherapy and thermoherapy.
Progresso Medico, 46: 57, 1990 Roma.
2) G.M. Pigliucci,F. Giudiceandrea, D.Venditti, V. Cervelli e Casciani C.U.
Optimization of Pre-Intra and Postoperative Hyperthermic treatment in Inoperable Lower Bowel and Liver Tumors.
Oncology, 50, 390-92, 1993.
3) G.M. Pigliucci, B. Iorio, D. Venditti, R. Fiorito, V. Cervelli, V. Vittorini,F. Giudiceandrea and C.U. Casciani.
The thermotherapy: A method increasing the effect of multidisciplinary treatment of cancer.
The 2nd All-Union Symposium with International Participation Hyperthermia in Oncology
Minsk , Urss, May 30-31, 1990
4) Pigliucci G.M., Venditti D., Giudiceandrea F., Maggiulli G., Cervelli V., Campioni M., Pisani A., Cervelli G., Iorio B. Casciani C.U.
Un Moderno approccio terapeutico nei tumori inoperabili del fegato: l'associazione chemio-embolizzazione distrettuale ed ipertermia.
Atti del 95 Congresso nazionale della Societa' Italiana di Chirurgia, Milano, 17-20 ottobre, 1993.
5) Pigliucci GM, Pochini M, Giudiceandrea F, Maggiulli G, Cervelli V, Casciani CU, Diamantini S, Fox U.
Our experiences and new perspective in interstitial microwave hyperthermia.
Abstract Book 18th International Symposium on Clinical Hyperthermia,
may 21-24 1995, Kiev , Ukraine .
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