In This paper we clarified the efficacy of thermochemotherapy using several anti-cancer agents such as MMC and 5'-DFUR in experimental animal models. The effective anti-tumor effect which was estimated by the rate of shrinkage of tumor and histopathological changes were observed. Especially, liposome MMC were advantageous type of agent with heating compared with native MMC. The intratumor concentration of these agents were examined to clarify the mechanism of enhancement of anti-tumor effect. These results suggest that the concentration of anticancer agent was affected with the dose of agent, the route and timing to administrate. For example several different results about the concentration of 254S were reported previously. Therefore when thermochemotherapy are performed, it is important to determine the exact dose of agent and timing to administrate.
On the other hand clinically randomized control study is need to prove the efficacy of thermochemotherapy, but actually it is impossible to perform this study due to the difference of patient's general condition, primary tumor present site and interruption of treatment by side effects. Therefore in this study matched control study was used for gastric cancer, pancreas cancer and colonic cancer to evaluate the efficacy of this therapy. The advantageous efficacy was demonstrated on the point of the shrinkage of tumor, life span, performance status and alleviation of pain and tumor histopathological changes. In addition of this results, sixty nine patients out of 90 (77%) had no side effect.
In conclusion that thermochemotherapy is one of the useful therapy for cancer in multi-disciplinary approach.

View full abstract

What kinds of instruments are required in the future ?
(1) Instruments for simultaneous thermotherapy and radiotherapy.
Simultaneous thermotherapy and radiotherapy achieve the most effective antitumor effect. As normal tissue sensitivity is also increased, selective radiotherapy and thermotherapy delivery to the tumor is necessary. We obtained good results in treating pancreatic and esophageal cancers with simultaneous thermotherapy and radiotherapy.
(2) Instruments effecting at least 45 C in tumors only.
This treatment is only effective for small tumors at 2-3 cm, in which case thermotherapy alone may be an effective teratment.
(3) Instruments effective for lung cancer.
Apart from surgery, other treatments for lung cancer are ineffective.
Some Japanese facilities are experimenting with combined Rf capacitive thermotherapy and radiotherapy for lung cancer.
Although the result is better than radiotherapy alone, a satisfactory level has not been reached. RF capacitive heating is not the best suited delivery system for lung cancer. Instruments that achieve effective hyperthermia in lung cancer await development.
The future of thermotherapy depends on the development of effective instruments, for which the responsibility of engineers is great.

View full abstract

Non-invasive temperature imaging methods using proton MRI were reviewed with respect to the temperature-dependent parameters, thermal equilibrium magnetization (with the effect of proton density) (M₀'), spin-lattice relaxation time (T₁), spin-spin relaxation time (T₂), diffusion coefficient (D) and proton chemical shift (δ). Although the temperature relations of M₀', T₁, T₂ and D of the water proton are clear in pure water (-0.36% /°C for M₀', 2.2% /°C for T₁, T₂ andD at 40°C), it was observed that the temperature relations have remarkable differences in tissues. On the other hand, it was found that the temperature relation of the proton chemical shift are similar (of the order of - 0.01 ppm/°C) between pure water and the different tissues. In addition, the proton chemical shift is the only parameter derived from the signal frequency, and therefore can be detected independently from the other parameters. For these reasons, the proton chemical shift method is deemed superior. The author and his colleagues have proposed two different temperature imaging modalities, the spectroscopic imaging (SI) and phase mapping (PM) methods, using the water proton chemical shift. The typical images of temperature distribution changes in an anesthetized rat obtained by the SI and PM methods were exhibitied. The PM method for temperature imaging during focused ultrasound sonication was introduced as a state-of-the-art technique for non-invasive temperature monitoring during thermotherapy.

View full abstract

The cytotoxic properties of hyperthermia combined with mitomycin C, and cis-diammine dichloroplatinum (II) and its derivatives (254-S, CBDCA, NK-121, ADWA-2114R) were studied in vitro monolayer cultures and multicellular spheroids of human malignant melanoma and colon carcinoma cells. In exponentially growing monolayer cells, marked hyperthermic sensitization was observed by all the drugs studied. When spheroids were treated with drugs and hyperthermia, the degree and characteristics of heat sensitization differed from those in monolayer cells. These results suggest that the microenvironment factor within spheroids may significantly affect the cytotoxicity of MMC and platinum complexes combined with hyperthermia.

View full abstract

This is a retrospective multi-institutional study on clinical hyperthermia of uterine cancers by the study group of the Japanese Society for Therapeutic Radiology and Oncology (JASTRO). There were 111 cases of uterine cancers collected from 10 hospitals. Included were 40 cases of stage III b squamous cell carcinomas, 18 of stage IV a and 40 recurrent cases. They were irradiated in a conventional way and hyperthermia was performed once or twice a week using Thermotron RF-8, Thermox1000, BSD1000, ERS100A and HMS-020 after a completion of daily irradiation. The intratumoral temperature was kept at 41-43°C for 30-40 minutes. In the stage III b, CR was obtained in 58% (23/40) and PR in 35% (14/40), while in stage IV a CR was 39% (7/18) and PR in 55% (10/18). Cumulative 5-year survival rate was 65.2% in stage III b and 37.3% in the stage IVa. In recurrent cases, response rate was 50% (14/28) by external heating and 100% (12/12) by intracavitary heating. Hyperthermia combined with radiotherapy is beneficial to the patients with stage III b and IV a cervical cancers and recurrent tumors.

View full abstract

From February 1991 to May 1995, we performed whole-Body hyperthermia (WBH) therapy 954 times in a total of 167 patients with advanced carcinoma using the U. S. by Enthermics Medical Systems Inc. At this time, we report our assessment of the efficacy of treatment in 112 patients who completed more than one course of WBH therapy. The therapy was performed in 52 male and 60 female patients aged 2080 years. Primary Carcinoma were the lung, colon, breast, stomach, kidney, uterus, liver, ovary, pancreas and others. The therapy was generally once a week performed in outpatients, who were given one course (4 times). The patients received intravenous anesthesia to achieve a somnolent state during the warming-up stage. Body temperature was measured in the esophagal, intrarectaly and at four sites of the body surface. The patients received WBH therapy for one hour (three to four hours for a complete course) with intraesophagal temperature maintained at 41.8°C. To judge the efficacy of the therapy, evaluation was made based on systemic criteria assessed by methods including the Karnofsky Index in addition to the UICC that was generally in use. A survey was conducted also to assess the rating of improvement in Quality of Life (QOL) through questionnaires. The efficacy rate according to the UICC was 75% for “significantly effecticve” together and “effective” and the using the systemic criteria was 81.3% in total. Improvement in QOL was evaluated in three stages : “excellent”, “good” and “no change”. QOL was rated as “excellent” or “good” by 78.5% of the patients. The efficacy rating used systemic criteria was higher than that used the UICC ; This was considered to result from an improvement in the Karnofsky Index due to recovery from pain. It was suggested that both the QOL evaluation and the systemic criteria were effective for judging the efficacy of this therapy, which led to a significant recovery of activity due to improvement in general condition.

View full abstract

Hsp72 is one of the stress proteins induced transcriptionally by various stressors such as heat, UV, ionizing radiation and DNA damaging agents. Many studies have shown a positive relationship between thermosensitivity/thermotolerance and heat shock proteins. On the other hand, cisplatin (cis-diamminedichloroplatinum (II)) is one of the chemotherapeutic agents which are widely effective against human cancers. The cytotoxicity of cisplatin is believed to be due to the formation of DNA adducts, which include mainly inter-and intra-strand DNA crosslinks. Many investigators have shown the cytotoxic effect of cisplatin enhanced by combination with hyperthermia. There are two possible modes of the interaction between hyperthermia and cisplatin. One is an increase of the drug uptake by hyperthermia, which may cause much more DNA damage in cells. The other is that hyperthermia may inhibit the repair of cisplatin-induced DNA damage as is the case in the combination of ionizing radiation and hyperthermia.
In the present study, we show the accumulation of hsp72 induced by cisplatin and the suppression of hsp72 accumulation by the combined treatment with hyperthermia and cisplatin, suggesting the third possible mode of interaction between hyperthermia and cisplatin which cisplatin suppresses the heat-induced hsp72 accumulation. These results suggest that the synergistic cytotoxic enhancement by the combination of hyperthermia and cisplatin may be dependent on the suppression of heat-induced hsp72 accumulation by cisplatin.

View full abstract

A non-contact microwave applicator was able to succesfully heat the posterior part of the retina near the optic disc of rabbits. The calculated temperature coincided with the actual measurment. The conventional Lagendijk type applicat does not heat sufficiently the posterior part of the retina. Our system cooled the anterior part of the eyeball of rabbits with water bolus. Microwave frequency was 2450MHz. The eyeball SAR (Specific Absorption Rate) distribution and its circumferential temperatures (boundary conditions) were measured using thermistors resistant to microwave irradiation (ACT). The temperature distribution in an eyeball sagital cross section was calculated using the finite element method. Calculated results were obtained from the SAR profile and boundary conditions. The calculated temperature at the midpoint of the eyeball was almost the same with the value measured by the ACT. The temperature of posterior part of the retina increased moderately. This method appears promising for safe and effective hyperthermic therapy of retinoblastoma.

View full abstract