A phase I and II clinical trial of a newly developed ultrasound hyperthermia system with an improved planar transducer.

PURPOSE: The clinical usefulness of a newly developed ultrasound hyperthermia system was evaluated. METHODS AND MATERIALS: The hyperthermia system uses a modified planer transducer operated at frequencies of 0.5, 1.0, and 1.5 MHz. The transducer has a nonvibrating part at the center to reduce the central hot spot. Frequency sweeping technique is also used to eliminate the annular hot spot around the center. Thirty-eight tumors in 29 patients were examined in this study. In 35 tumors, hyperthermia was given in conjunction with irradiation and/or chemotherapy, and in the remaining 3 tumors, hyperthermia alone was given. In all, a total of 153 hyperthermia sessions were performed. RESULTS: The number of hyperthermia sessions per tumor ranged from 1 to 7 (mean, 4.0 +/- 1.3). The number of intratumor thermometry points per session ranged from 1 to 8 (mean, 4.3 +/- 1.5). The average intratumor temperature for tumors with a maximum depth of <3 cm, 3-6 cm, and >6 cm was 42.1 +/- 1.2, 41.7 +/- 1.4, and 39.9 +/- 2.0 degrees C, respectively. The percentage of monitored intratumor points with temperature exceeding 42 degrees C was 56 +/- 31%, 43 +/- 34%, and 21 +/- 24%, respectively. Of the 30 evaluable tumors treated with combined irradiation, 12 showed complete response, 14 partial response, and 4 no change. Observed complications included pain at the treatment site in 13 of the 153 treatment sessions and vesicle formation in 3 of the 38 treatment sites. No serious complication was seen. CONCLUSIONS: These results indicate that the newly developed ultrasound hyperthermia system is clinically useful for the treatment of localized superficial and subsurface tumors with a maximum tumor depth of no more than 6 cm.

Thermoradiotherapy of superficial and subsurface tumours: analysis of thermal parameters and tumour response.

Between 1988 and 1993, 57 superficial and subsurface tumours of various tumour type were treated with a 430-MHz microwave heating device. Mean (range) tumour depth of the 57 tumours was 3.0 (0.5-6.5) cm. Fifty-four tumours were treated with thermoradiotherapy. Total radiation dose ranged from 20 to 70 Gy with a mean of 53 Gy. For the remaining three tumours, thermochemotherapy was performed. Hyperthermia was given once a week, and a total of 207 heat sessions was administered. Our goal of hyperthermia treatment was to elevate all monitored tumour points > 41 degrees C for > 30 min. The mean (range) number of intratumoral thermometry points was 3.7 (2-6). The goal of hyperthermia treatment was achieved in 49% of the sessions. At the time of maximum tumour regression, complete response was noted in 53% of the tumours treated with thermoradiotherapy. Univariate analysis demonstrated that parameters including tumour type (breast cancer versus others), tumour depth, minimum tumour temperature, average tumour temperature, minimum equivalent time at 43 degrees C, and number of heat sessions achieving the treatment goal significantly affected the tumour response of the combined treatment, while total radiation dose and number of heat sessions were not significant factors for tumour response. Multivariate logistic analysis revealed that only tumour depth (< 3 versus > or = 3 cm) was a significant prognostic factor for tumour response (p = 0.029). Tumour type (breast cancer versus others) and a number of heat sessions achieving the treatment goal (0-1 versus 2-5) were found to be of borderline significance in the multivariate analysis (p = 0.075 and 0.097 respectively). The number of heat sessions achieving a minimum tumour temperature of > 41 degrees C for > 30 min seems a practical thermal parameter that influences tumour response. The present study indicates the importance of quality and quantity of heat session on the treatment outcome of thermoradiotherapy.

Clinical experiences in the thermoradiotherapy for advanced gastric cancer.

Recurrent and/or inoperable gastric cancer has been treated by thermoradiotherapy at Kyoto University Hospital since 1983. In the present study, the efficacy of hyperthermia (using radiofrequency capacitive heating) plus radiotherapy for gastric cancer was evaluated in 21 patients with local recurrence, abdominal wall metastases, peritonitis carcinomatosis or paraaortic node metastases. The intratumour temperature was measured using a microthermocouple thermometer. The means of the maximum, average, and minimum intratumour temperature were 43.5, 42.1, and 41.1 degrees C respectively. The local tumour response was evaluated using computed tomography (CT). The local response rate (complete regression plus partial regression/all tumours) was 88.9%, which seemed to be higher than that of other reports using thermochemotherapy or radiotherapy alone. The one-year cumulative survival rate was 39.1%.

Clinical results of thermoradiotherapy for soft tissue tumours.

Thirty-one unresectable and/or recurrent soft tissue tumours in 27 patients underwent hyperthermia in combination with radiation therapy. Locoregional hyperthermia was administered once or twice a week for 40-60 min to a total of 2-14 sessions using RF capacitive or microwave heating equipment. Radiation therapy was given 10-20 min before hyperthermia at doses of 20.8 to 70 Gy. The mean +/- SD of the maximum, average, and minimum intratumour temperatures was 44.0 +/- 2.9 degrees C, 42.3 +/- 1.6 degrees C, 40.1 +/- 1.1 degree C respectively, and that of the percentage of the intratumour points that exceeded 41 and 43 degrees C was 66.0 +/- 33.6, and 31.0 +/- 26.1 respectively. Of the 31 tumours treated, 13 (42%) showed CR (complete regression), 10 (32%) PR (> 50 and < 100% regression) and 8 (26%) NC (< 50% regression). Since intratumour low density areas on post-treatment CT scans have been demonstrated to be a useful parameter for assessing tumour response to thermoradiotherapy, the presence of low density areas was also assessed. Low density areas were classified into the following three categories according to the percent area occupied in the maximal cross-section of the tumour: type I, < 50%, type II, 50-80%; type III, > 80%. Of 20 tumours evaluable, 6 (30%) exhibited type III change, 11 (55%) type II and 3 (15%) type I. All of the type III tumours demonstrated a marked response on follow-up or histopathological examination. The major complication associated with treatment was skin ulcer in two patients. The five-year survival of the total 27 patients and 18 patients who had no distant metastases at the start of treatment was 32 and 48% respectively. These results indicate the clinical benefit of thermoradiotherapy using RF capacitive or microwave equipment for locally advanced and/or recurrent soft tissue tumours.

Clinical evaluation of 430 MHz microwave hyperthermia system with lens applicator for cancer therapy.

The clinical efficacy of a microwave (MW) hyperthermia system using an electric-field converging (lens) applicator is evaluated for 42 malignant tumours with a maximum tumour depth of less than 7 cm. The mean of the maximum, average and minimum tumour temperature of the 42 tumours are 44.5, 42.5 and 40.7 C, respectively. The thermal parameters are higher for tumours in the chest, abdominal walls and hip than for those in the neck, groin and extremities. No apparent difference in thermal parameters according to the depth of tumour is shown. Of 40 tumours treated by hyperthermia in combination with radiotherapy, 20 (50%) showed complete regression, 14 (35%) showed partial regression, and six (15%) showed no change. This phase I and II study indicates clinical feasibility of the newly developed MW heating apparatus, and strongly suggests the usefulness of thermoradiotherapy in the treatment of localised superficial and subsurface malignancies.

Development of intra-arterial hyperthermia using a dextran-magnetite complex.

Dextran-magnetite complex (DM) is a colloidal sol of subdomain magnetite particles (i.e. a 'magnetic fluid'). The specific absorption rate of DM in an AC magnetic field is much higher than those of multidomain ferrite particles due to its different mechanism of heat generation. We designed two DM-containing embolic materials (a DM/Lipiodol emulsion and a DM/degradable starch microsphere suspension) to heat target tissues with the use of an external AC magnetic field. In vitro experiments showed that the heat-generating capacity of DM was not reduced in these mixtures. When these materials were injected into the renal arteries of Japanese white rabbits, they both achieved embolization of the artery and selective heating of the embolized kidney by exposure to a 100 kHz AC magnetic field of approximately 15,000 A/m. Histological examination showed a homogeneous distribution of DM in the embolized kidney. These results suggest the possibility of using DM-containing embolic materials for inductive hyperthermia.

Drug dissolution from indomethacin-starch hybrid powders prepared by the dry impact blending method.

Indomethacin was hybridized with potato starch using a dry impact blending method. Resultant hybrid powders were investigated by scanning electron microscopy and X-ray powder diffraction. Amorphous indomethacin spread over the starch surface in a layer immediately after being hybridized, and then gradually reverted to fine crystalline particles adhering firmly to the starch surface. Indomethacin dissolution from the hybrid powder was compared with those from physical mixtures and granules taken from a commercially available capsule. Indomethacin dissolution from powder and capsule dosage forms, even in an acidic medium, was drastically accelerated by the hybridization.

[Current status of thermoradiotherapy in cancer therapy].

The current status of thermoradiotherapy for cancer is reviewed. The usefulness of this combined treatment for superficial tumors, in which heating and thermometry are relatively easy to apply, has been clearly demonstrated by many clinical results. With recent technological advancements, the application of thermoradiotherapy to deep-seated tumors is increasing, and encouraging results have been reported for various tumors including brain tumors, carcinomas of the breast, lung, esophagus, liver, rectum, urinary bladder, and soft tissue tumors. Thermoradiotherapy seems a very promising treatment modality for various refractory malignancies.

Quercetin, an inhibitor of heat shock protein synthesis, inhibits the acquisition of thermotolerance in a human colon carcinoma cell line.

Here, we describe the effects of quercetin on the induction of thermotolerance as examined by colony forming assay in a cell line derived from human colon carcinoma (COLO320 DM). Cells became resistant to heat treatment at 45 degrees C when they were preheated at 42 degrees C for 1.5 h or at 45 degrees C for 10 min. This induction of thermotolerance was almost completely inhibited by continuous treatment with 100 microM quercetin during the first and second heating sessions, and the interval between. This effect of quercetin was demonstrated to be dose-dependent over a concentration range of 50-200 microM. Quercetin did not increase the thermosensitivity of non-tolerant cells. The presence of quercetin during the first conditioning heating was more effective in inhibiting thermotolerance than its presence during the second heating. Quercetin was also found to inhibit the acquisition of thermotolerance induced by sodium arsenite. Cycloheximide, a nonspecific inhibitor of protein synthesis, did not affect the acquisition of thermotolerance by the same cell line. Quercetin specifically inhibits the synthesis of all heat shock proteins so far reported previously, and this leads to inhibition of the induction of thermotolerance. Such inhibition of thermotolerance by quercetin may improve the efficacy of clinical fractionated hyperthermia.

[Clinical assessment of thermoradiotherapy of breast cancer and cancer of the urinary bladder].

Non-randomized clinical trials of thermoradiotherapy for breast cancer and carcinoma of the urinary bladder were reported. Thermoradiotherapy was useful for breast cancer treatment in term of (1) increased local control for locally advanced tumors and (2) possibility of reducing dose of irradiation for recurrent tumors following radiotherapy. Tumor response to thermoradiotherapy was dependent on tumor volume and maximum or minimum tumor temperature. Thermoradiotherapy was also effective as a preoperative-treatment for urinary bladder cancer. The incidence of down-staging and degeneration of tumors was significantly higher in thermoradiotherapy than in radiotherapy. These effects were temperature dependent. Patients with T 3-4 NOMO or Grade 3 tumors treated with thermoradiotherapy showed a tendency of increased survival compared with those treated with radiotherapy alone.

Preparation of drug-diluent hybrid powders by dry processing.

New hybrid powders have been produced by the dry processing of six drugs (oxyphenbutazone, prednisolone, theophylline, indomethacin, phenacetin and aspirin), with potato starch used as a core material, by means of an electric mortar and a powder surface reforming system designed to produce hybrid powders. The hybrid powders obtained immediately after production differed in their structure from interactive mixtures. With the hybrid powders the drug was spread on the surface of the core particle by friction and collision that occurred in the dry process, but with interactive mixtures the drug simply adhered as intact particles to the surface of diluent particles. Scanning electron microscopy and powder X-ray diffractometry indicated that the mechanochemical phenomenon was essential for the production of the hybrid powders. With time, a shape change in the adhering drug was observed as a relaxation process took place, with recrystallization resulting from the release of accumulated energy. The change with time might depend upon the method of producing powders and the physical properties of the drug used, e.g. the smooth layer of indomethacin produced by the powder surface reforming system reverted to fine particles tightly adhering to the starch surface, though no change was observed with prednisolone.

Intestinal absorption of oyster shell electrolysate.

High voltage electric current was passed through oyster shell powder for electrolysis. The crystalline shape of oyster shell electrolysate appeared to be quite different from that of CaO or CaCO3. Higher serum calcium values were achieved by oral administration of the same amount of as oyster shell electrolysate than as calcium carbonate in vitamin D-deficient rats, suggesting a better intestinal absorption of the former than the latter. In four patients with postoperative hypoparathyroidism with reduced intestinal calcium absorption, the same amount of elementary calcium as oyster shell electrolysate was more effective than calcium carbonate in raising serum calcium in the absence of vitamin D supplement. Oyster shell electrolysate was also more effective in suppressing serum parathyroid hormone concentration than calcium carbonate in two patients with secondary hyperparathyroidism with renal failure. Calcium thus appears to be more readily absorbed from oyster shell electrolysate than from calcium carbonate through intestinal barriers produced by insufficient vitamin D action.