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Purpose: To evaluate the contribution of the thermal dose parameters during regional hyperthermia (HT) treatment to the clinical outcomes in patients with cervical carcinoma (CC) who received chemoradiotherapy (CRT) plus HT., Materials and Methods: Data from a multicentre randomised clinical trial of concurrent CRT + HT vs. CRT alone were used to evaluate the efficacy and safety of this combination therapy in the CC patients. The intrarectal temperatures of patients undergoing HT were recorded. The complete thermal data of 47 (92%) of the 51 patients in the CRT + HT group were available for the thermal analysis. Thus, 47 patients who received CRT + HT were included in the present study., Results: Among the patients who received CRT + HT, a higher CEM43T90 (≥1 min) value (a thermal dose parameter) was significantly associated with better local relapse-free survival in both univariate (p = 0.024) and multivariate (p = 0.0097) analyses. The disease-free survival of the patients with higher CEM43T90 (≥1 min) values tended to be better in comparison to patients with lower CEM43T90 (<1 min) value (p = 0.071). A complete response tended to be associated with the CEM43T90 (p = 0.056). Disease-free survival, local relapse-free survival and complete response rate for patients with higher CEM43T90 (≥1) were significantly better than those for patients with CRT alone (p = 0.036, p = 0.036 and p = 0.048)., Conclusions: Dose-effect relationships between thermal dose parameters and clinical outcomes were confirmed in the CC patients treated with a combination of CRT + HT. This study also confirmed that HT with lower CEM43T90 is insufficient to achieve a significant hyperthermic sensitisation to CRT.

Purpose: To evaluate the effectiveness of whole-pelvic hyperthermia (HT) added to standard chemoradiotherapy (CRT) in locally advanced cervical cancer (CC), by investigating the clinical response and survival of patients treated with cisplatin-based CRT vs. CRT with HT (CRT + HT)., Materials and Methods: This study was conducted at five hospitals in Japan between September 2001 and March 2015 in patients with the International Federation of Gynecology and Obstetrics stage IB (bulky)-IVA CC undergoing definitive CRT. After giving a written informed consent, patients were randomly allocated to two treatment groups: CRT and CRT + HT group. Overall survival (OS), disease-free survival (DFS), local relapse-free survival (LRFS), complete response (CR) rate and tolerability were evaluated., Results: In total, 101 patients were treated. Patient characteristics, total dose of cisplatin and radiotherapy were similar for both groups. Although not statistically significant, the 5-year OS, DFS and LRFS in the CRT + HT group (77.8%, 70.8% and 80.1%, respectively) were better than those in the CRT group (64.8%, 60.6% and 71.0%, respectively). CR was significantly more likely to be achieved in patients in the CRT + HT group than in the CRT group (88% vs. 77.6%; adjusted odds ratio, 3.993; 95% confidence interval, 1.018-15.67; p = .047). CRT + HT was well tolerated and caused no additional acute or long-term toxicity compared with CRT alone., Conclusions: HT combined with CRT improved the CR rate of CRT in patients with locally advanced CC, however, could not improve survival outcomes. Further studies in larger samples are warranted.

We developed a new hybrid gel phantom using carrageenan and gellan gum for the purpose of visualizing three-dimensional temperature distribution. The phantom, which contains carrageenan, gellan gum, non-ionic surface active agent, potassium chloride, n-butanol, sodium azide, and water, shows good transparency at room temperature, and has the advantage that the heated region becomes white and opaque due to segregation of the surface active agent. Carrageenan and gellan gum were added to improve the transparency and fragility of the hybrid gel. Potassium chloride was used to adjust the electrical conductivity of the gel to a range of 5-130 MHz, so that it would be equivalent to that of muscle tissue for each frequency used by electromagnetic heating devices. N-butanol was used to adjust the clouding temperature to a range between 45 and 55 degrees C. In the present study we clarified the important properties of the new phantom, and developed formulae for easy determination of the amounts of ingredients necessary for the desired clouding temperature and electric conductivity. The characteristics of this phantom are: a) a solid form to avoid convection by heat conduction; b) sufficient strength without fragility to form a torso without the use of a reinforcing agent; c) high transparency at room temperature and visualization of the heating area as a white turbidity; d) time-lapse and accurate visualization of the changing temperature area without thermal hysteresis; e) electrical properties similar to those of human tissues; f) ease of production; and g) low cost and good safety. This phantom might assist oncologists in their routine checking and study of the performance of electromagnetic heating devices for hyperthermia and radiofrequency ablation.

The authors developed a phantom, designated as the CAGN phantom, compatible for MRI and hyperthermia that is useful in the fundamental studies of non-invasive MR thermometry. The ingredients of this phantom are carrageenan, GdCl3 as a T1 modifier, agarose as a T2 modifier, NaCl as a conductivity modifier, NaN3 as an antiseptic and distilled water. Another phantom that was developed, the CAG phantom, has relaxation times that are adjustable to those of any human tissue. To use this phantom for electromagnetic heating, NaCl was added to change the conductivity of the phantom and clarified the relationship between the conductivity and NaCl concentration. This study examined the relationship between relaxation times and NaCl concentration of the CAGN phantom. The results showed that both T1 and T2 values were affected by NaCl and the experimental results led to the empirical formulae expressing the relationship between the relaxation rates (1/T1, 1/T2) and the concentrations of GdCl3, agarose and NaCl. The appropriate concentrations of T1 and T2 modifiers were calculated from these empirical formulae when making a specified phantom that has the required relaxation times and NaCl concentration.

A phantom has previously been developed containing carrageenan, agarose and gadolinium chloride (called CAG phantom) for MRI with 1.5 T. T(1) and T(2) relaxation times of this phantom are independently changeable by varying concentrations of relaxation-time modifiers to simulate relaxation times of the various types of human tissues. The CAG phantom has a T(1) value of 202-1904 ms and a T(2) value of 38-423 ms, when the GdCl(3) concentration is varied from 0-140 micromol/kg and the agarose concentration is varied from 0-1.6%. A new phantom has now been developed (called CAGN phantom), made by adding an electric conductive agent, NaCl, to the CAG phantom for use in the areas of MRI and hyperthermia research. Dielectric properties of the CAGN phantom were measured and the results of experiments were expressed by the Cole-Cole equation in the frequency range of 5-130 MHz. The relationship between the conductivity of the CAGN phantom and the concentration of NaCl was expressed by a linear function in the frequency range of 1-130 MHz. The linear function involves a parameter of frequency and, when the frequency is 10 MHz, the conductivity of the CAGN phantom can be changed from 0.27-1.26 Sm(-1) by increasing the NaCl concentration from 0-0.7%. The CAGN phantom developed can be employed in basic experiments for non-invasive temperature measurement using MRI and as a loading phantom for MRI with up to 3 T.

Cepharanthine (Ce) is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata. In our previous study, Ce significantly enhanced thermosensitivity and thereby reduced thermotolerance in vitro, and intra-peritoneal injection of Ce slightly enhanced thermosensitivity in vivo. In the present study, we investigated Ce's effect in vitro on the pattern of cell death after heating and the effect of intra-tumoral injection of Ce on in vivo thermosensitivity using a mouse fibrosarcoma, FSa-II, and C3H/He mice. Ce significantly enhanced the in vitro thermosensitivity of FSa-II cells with heating at 44 degrees C, with increased Ce concentration. Time-lapse microscopic observation of individual cells confirmed that Ce treatment hastened both apoptosis (specifically, apoptotic budding) and necrosis (as indicated by staining with propidium iodide). Staining with annexin V-enhanced green fluorescent protein indicated that Ce used concomitantly with heating significantly increased the proportion of cells in the early stage of apoptosis. Ce combined with heating also significantly increased the proportion of cells with high intracellular caspase-3 activity, as detected by a substrate of caspase-3, PhiPhiLux-G1D2. The intra-tumoral injection of Ce, followed by heating at 44 degrees C, significantly delayed in vivo tumor growth, and this delay increased in a Ce concentration-dependent manner. Ce injected 30 min before heating delayed tumor growth more than Ce injected immediately before heating. These findings suggest the potential of Ce as a thermosensitizer to increase apoptosis of tumor cells.

We report herein the effects of p53 gene therapy in the radiotherapy or thermotherapy of eight human head and neck squamous cell carcinoma (SCC) cell lines. The discrepancy between radiosensitivity combined with p53 gene therapy than that without p53 gene therapy increased among the eight SCC cell lines. The discrepancy increased in the thermosensitivity at 43 degrees C and decreased in that at 44 degrees C among the eight SCC cell lines. Thus, the p53 gene therapy did not always improve the discrepancy between radiosensitivity and thermosensitivity in the eight SCC cell lines. In the radiotherapy combined with adenoviral p53 gene therapy, the survival rates of three of eight SCC cell lines decreased, and that of only one cell line increased compared with radiotherapy alone. In thermotherapy combined with p53 gene therapy, the survival rates of three at 44 degrees C and five at 43 degrees C of the eight SCC cell lines decreased, although only one cell line at 43 degrees C increased its survival rate compared with thermotherapy alone. The p53 gene therapy decreased the survival rates of both radiotherapy and thermotherapy in three of eight SCC cell lines. Further, the distribution of plots on the basis of the time for 10% survival of radiotherapy and the dose for 10% survival of thermotherapy with p53 gene therapy shifted to the lower left side of the plots compared with those without p53 gene therapy. These findings indicated that p53 gene therapy improves the effects of both radiotherapy and thermotherapy.

It has been shown that hyperthermia can enhance the cytotoxicity of some chemotherapeutics. However, the most effective agent(s) at elevated temperatures have yet to be determined. A previous study suggests that the drug of choice at elevated temperatures may be different from that at the physiological temperature, and that the alkylating agents may be most effective at elevated temperatures. To further investigate these possibilities, the effect of chemotherapeutic agents were compared. These agents were cyclophosphamide, ifosfamide, melphalan, cis-diamminedichloroplatinum (II), 5-fluorouracil, mitomycin C and bleomycin. Three tumours (mammary carcinoma, osteosarcoma and squamous cell carcinoma) were used. They were transplanted into the feet of C3H/He mice. When tumours reached 65 mm(3), a test agent was injected intraperitoneally. Tumours were immediately heated at 41.5 degrees C for 30 min, and the tumour growth (TG) time was studied for each tumour. Using the TG times, the TG-50 (the time required for one-half of the total number of the treated tumours to reach the volume of 800 mm(3) from 65 mm(3)) was calculated. Subsequently, the tumour growth delay time (GDT) and the thermal enhancement ratio (TER) were obtained. The GDT was the difference between the TG-50 of treated tumours and that of non-treated control tumours. The TER was the ratio of the GDT of a group treated with an agent at 41.5 degrees C to that of a group treated with the agent at room temperature. Results showed that the top three effective agents tested at 41.5 degrees C were solely alkylating agents--CY, IFO and L-PAM--for each kind of tumour. A GDT of cisplatin was smaller than those of the alkylating agents. The smallest TER, 1.1, was observed for 5-fluorouracil, which was given for mammary carcinoma, and for mitomycin C, which was given for squamous cell carcinoma. It could be concluded that the alkylating agents at elevated temperatures might be the drugs of choice for many types of tumours. The possible mechanisms of thermal enhancement associated with these agents are discussed.

We report on thermoradiotherapy combined with p53 gene therapy in the human salivary gland adenocarcinoma cell line HSG. HSG cells were successfully infected at a rate of 62.3% with MOIs of 20 of either AxCAip53 or AxCAiLacZ. The AxCAiLacZ did not inhibit the survival of the HSG cells. The survival fractions of AxCAip53-infected HSG cells were lower than those of the AxCAiLacZ-infected HSG cells, but there was no significant difference (p=0.30). AxCAip53 decreased the survival rates of thermotherapy (43 degrees C; p=0.084 and 44 degrees C; p=0.18), radiotherapy (6 Gy; p=0.20) and thermoradiotherapy (6 Gy plus 43 degrees C; p=0.24 and 6 Gy plus 44 degrees C; p=0.96), but there were no significant differences. In comparing the survival rates of thermoradiotherapy with those of thermotherapy and radiotherapy, thermoradiotherapy, regardless of the combination with p53 gene therapy, demonstrated actual survival rates lower than theoretical survival rates based on survival rates of thermotherapy multiplied by survival rates of radiotherapy. This result indicates that thermoradiotherapy is effective in the treatment of HSG cells. Thermoradiotherapy combined with p53 gene therapy was the most effective therapy among the combinations of therapies demonstrating that thermoradiotherapy combined with p53 gene therapy may be a useful tool in the treatment of HSG cells.

Thermoradiosensitivity of 8 cell lines of head and neck squamous cell carcinoma (HO-1-u-1, HSC2, HSC3, HSC4, SAS, KB, Hep2, and Ca9-22) was investigated. The differences of radiosensitivity between the cell line with the highest radiosensitivity and the cell line with the lowest radiosensitivity were 1.7-, 7.7-, and 41-fold at 2, 6 and 8 Gy, respectively. The differences between the cell line with the highest thermosensitivity and the cell line with the lowest thermosensitivity were 2.4-, 6.2- and 34.4-fold at 43 degrees C for 40, 60 and 100 min, and 2.6-, 4.9- and 127-fold at 44 degrees C for 20, 30 and 50 min, respectively. These findings indicated that there were large differences in both radiosensitivity and thermosensitivity among the 8 cell lines. There was a negative relationship between radiosensitivity and thermosensitivity (43 degrees C: r=-0.600, 44 degrees C: r=-0.848) in 7 of 8 cell lines, the exception being the HSC4 cell line, which was resistant to both therapies. Four of the 8 cell lines at 43 degrees C and 5 at 44 degrees C in the radiotherapy combined with thermotherapy showed actual survival rates smaller than the theoretical survival rates. Thus, thermoradiotherapy was deemed effective in the head and neck carcinoma cell lines, although 1 of 8 cell lines was resistant to both radiotherapy and thermotherapy.

We report on thermochemotherapy in a human salivary gland adenocarcinoma cell line. Hyperthermia reduced the survival rate to 50 and 20% by heating at 43 degrees C for 40 and 60 min, respectively, and is by itself useful in human salivary gland carcinoma treatment. Adriamycin, cisplatin, and mitomycin C can possible be used clinically, while bleomycin and 5-fluorouracil cannot, to treat this carcinoma. The optimal temperature was considered to be 41 degrees C in adriamycin, 42 degrees C in cisplatin, 37 degrees C in mitomycin C, and 42 degrees C in bleomycin in the thermochemotherapy. Thermochemotherapy is a useful tool in the treatment of human salivary gland carcinoma cells, but it is necessary to select the best anticancer drugs and the optimal temperature for optimal success using this treatment.

The variations of the specific absorption rate (SAR) and thermal distribution in the JSHO QA phantoms were investigated by radiofrequency (RF) capacitive intracavitary hyperthermia (ICHT) applicator (AP-T01, Omron Electric Co., Kyoto, Japan) with the changing position of the opposite flat applicator (15-cm in diameter). The thermal distribution was observed with the thermographic camera and the normalized SAR distribution was calculated with the thermal data that were measured with the thermocouple thermometers. The SAR and thermal distributions of AP-T01 significantly varied with the position of the opposite flat applicator. The slope of the normalized SAR became gradual towards the side of the flat applicator. During the operating of a high flow rate (1500 ml/min) cooling system, the region between AP-T01 and the flat applicator was widely and rather homogeneously heated, except the hot spot around the end of AP-T01. This hot spot may be due to the imbalance of cooling of AP-T01 and the warming-up of the electrode. These results suggest that the RF capacitive ICHT using AP-T01 may be clinically effective on the deep-seated tumours in the direction of either the end wall, such as cervical cancers, or the upper wall, such as prostatic cancers and the mediastinal metastatic lymph nodes, if an improvement of the cooling system is achieved.

The variations of the specific absorption rate (SAR) and thermal distributions in the JSHO QA phantom were investigated by using the radiofrequency (RF) capacitive intracavitary hyperthermia (ICHT) applicator (AP-T01, Omron Electric Co., Kyoto, Japan) and the opposite flat applicators of different sizes (AP-75E: 7.5 cm in diameter, AP-100E: 10 cm in diameter, and AP-150E: 15 cm in diameter). The influences of the distance between both applicators were also investigated. Heating of the region between both applicators became weaker with the increase in size of the opposite flat applicator, and it became stronger with the decrease of the distance between both applicators. Heating near the flat applicator became weaker with the increase in size of the flat applicators, and it showed no apparent difference with the increase of the distance between both applicators. The normalized SAR values between AP-T01 and the opposite flat applicator became smaller and its slope became steeper with the increase in size of the opposite flat applicator and in the distance between both applicators. These results suggest that the variability of the specific absorption rate (SAR) and thermal distributions of the region between both applicators may show the potentiality of usefulness for heating the tumours of various sizes, shapes and location.

Cepharanthin (Ce) is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata. The results of our previous in vitro study indicated that Ce reduces thermotolerance by enhancing thermosensitivity. In the present study, we investigated the in vitro and in vivo effects of Ce on thermosensitivity and thermotolerance using a murine mammary carcinoma, MCa, and C3H/HeN mice. Ce enhanced the thermosensitivity of MCa cells for heating at 44 degrees C not only in vitro but also in vivo. The in vivo enhancement ratio +/- SD of Ce at 100 mg/kg for heating at 44 degrees C was 1.3+/-0.3. The fractionated heat treatments at 44 degrees C for 30 and 60 min with an interval time of 0-6 days resulted in the development of remarkable thermotolerance and the expression of heat shock protein 70 in MCa tumors after the first heating. Ce at 100 mg/kg given immediately after the first heating increased the expression of heat shock protein 70 in MCa tumors, and did not reduce the development of thermotolerance. Ce given immediately before the first or second heating also did not inhibit the thermotolerance. The results of this study suggest that Ce enhances the thermosensitivity of MCa tumors as a thermosensitizer, but that this mild thermosensitizing property of Ce might be insufficient to conquer the remarkable thermotolerance in MCa tumors that develops after the first heating.

Seventy-two patients with Stages III and IV (TNM, UICC, 1987) squamous-cell carcinoma of the oropharynx and hypopharynx (oro-hypopharyngeal cancer) were treated with external irradiation, or irradiation plus 13.56 MHz radiofrequency (RF) capacitive hyperthermia from 1989 to 1995. This study compared initial response, histological effect and 5-year survival rate of thermoradiotherapy (TRT) group with those of radiotherapy alone (RT) group. In the TRT group, 15 patients were treated definitively, and 18 patients preoperatively. In the RT group, 15 patients were treated definitively, and 24 patients preoperatively. With definitive irradiation, the complete response rate of the primary lesions was 73% in the TRT group and 27% in the RT group (p = 0.009) and the complete response rate of the metastatic lymph nodes was 80% in the TRT group and 27% in the RT group (p = 0.005). With preoperative irradiation, the pathological CR (No residual cancerous cells) rate of the primary lesions was 56% in the TRT group and 8% in the RT group (p = 0.01), and the pathological CR rate of the lymph nodes was 72% in the TRT group and 21% in the RT group (p = 0.001). The 5-year survival rates with definitive irradiation were 47.6% in the TRT group and 18.7% in the RT group (p = 0.025). Thus TRT was more effective than RT for advanced oro-hypopharyngeal cancer.

In the present study, the mechanism involved in the enhancement of adriamycin (ADR) accumulation by cepharanthin (CEP) and hyperthermia were examined. The accumulation of ADR and Fluo3 (an indicator of Ca2+) was increased by treatment with CEP. This suggests that ADR accumulation may increase due to increased influx of Ca2+. The ADR accumulation increased with increasing the KCl concentration in the presence of CEP when the KCl concentration was over 200 mM. This demonstrates that ADR accumulation increases with treatment with CEP and increasing the KCl concentration after the cell membrane potential reaches 0. ADR accumulation did not change with the extracellular pH in the absence of NaHCO3. CEP increased the ADR accumulation with increasing extracellular pH, regardless of NaHCO3. This suggests that CEP may affect the H+ flux, and consequently increase ADR accumulation regardless of NaHCO3. Further, it increased with increasing extracellular pH in the presence of NaHCO3, regardless of CEP. It is thought that the interaction between H+ and HCO3- may cause increased ADR accumulation. ADR accumulation was decreased by DIDS and amiloride at 37 degrees C. ADR accumulation in the presence of amiloride at 45 degrees C was increased compared with that at 37 degrees C. However, the accumulation combined with amiloride and hyperthermia was lower than with treatment with ADR only at 37 degrees C. This indicates that ADR accumulation is decreased by amiloride and increased by hyperthermia. ADR accumulation is further decreased by DIDS at 45 degrees C compared with 37 degrees C. This suggests that the H+ flux in hyperthermia is influenced by Cl-/HCO3- exchanger but not Na+/H+ exchanger.

We report the results of phase I/II studies of preoperative multidisciplinary treatment of 14 patients with soft tissue sarcoma using hyperthermia from November 1990 to April 1995. The preoperative treatment was conducted with thermo-radio-chemotherapy in 11 cases of stage III, and with thermo-radiotherapy as well as thermo-chemotherapy in three cases of stages I and II. Hyperthermia was carried out twice a week with totals ranging from 4 to 14 times (average: 8.4 times); each session lasted 60 min. Radiotherapy was administered four or five times per week, and the dose was 1.8 2Gy/fraction, with a total of 30-40 Gy in a four week period. Chemotherapy was mainly in the form of MAID regimen (2-mercaptoethanesulphonic acid (mesna), adriamycin, ifosfamide and dacarbazine). The tumors were surgically resected in all patients after completing the preoperative treatment. The efficacy rate, as expressed by the percentage of either tumors in which reduction rate was 50% or more, or tumors for which post-treatment contrast enhanced CT image revealed low density volumes occupying 50% or more of the total mass, was 71% (ten of the 14 tumors). The mean tumor necrosis rate in the resected specimens was 78%. The tumor necrosis rate was significantly high (P < 0.05) in patients whose Time > or = 42 degrees C was of long duration. Postoperative complications were observed in six patients; among these, two patients developed wound infection that required surgical treatment as a complication of surgery performed in the early stage following the preoperative treatment. After a mean postoperative follow-up of 27 months, distant metastasis occurred in four patients resulting in three fatalities. The three-year cumulative survival rate was 64.3%. No local recurrence was observed in any patient during the follow-up, thus confirming our hypothesis that preoperative multidisciplinary treatment has an excellent local efficacy. We think that it would be valuable to conduct, at many facilities, phase III studies on the treatment of soft tissue sarcoma by a combination of surgery and preoperative multidisciplinary treatment using hyperthermia, paying close attention to the interval between these two modalities.

The acquisition of resistance to anticancer drugs is an important problem in cancer chemotherapy. Ehrlich ascites tumor cells (wild type EAT cells) were grown in a medium containing 1 microgram/ml adriamycin (ADR) (ADR-resistant strain) and the cells that proliferated were established in our laboratory. Intracellular ADR accumulation and the killing effect of ADR in the ADR-resistant strain were markedly reduced compared with those of the wild type EAT cells. In this study, we initially observed thermosensitivity in both strains and found no difference in the thermosensitivity. These findings demonstrated that hyperthermic treatment was effective in the ADR-resistant strain as well as in the wild type EAT cells. On the other hand, thermotolerance is an important problem in the hyperthermic treatment of cancer. We next observed the thermotolerance of both strains and found that the thermotolerance in the ADR-resistant strain was greater than that in the wild type EAT cells, but the thermotolerance was almost restored within 24 hours. Furthermore, we investigated the influence of thermotolerance on the intracellular accumulation and killing effects of ADR in the wild type EAT cells. There was no difference in the intracellular ADR accumulation and the killing effect of ADR between non-thermoresistant cells and thermoresistant cells. These results suggested that hyperthermia was effective in the ADR-resistant cells either alone or combination with ADR.

We compared adriamycin (ADR) accumulation with the intensity of intracellular fluorescence of 3,3'-(di-n-hexyl)-2,2'-oxacarbocyanine iodide (NK-2280), an indicator of cell membrane potential, after hyperthermia and examined the effects of cepharanthin (CEP) on the accumulation of ADR and NK-2280 in wild and ADR-resistant strains of Ehrlich ascites tumour (EAT) cells. Among wild 0.2 and 1-microgram ADR-resistant strains of EAT cells, intracellular accumulation of both ADR and NK-2280 decreased with an increase of ADR resistance. Hyperthermia at 42 degrees C and CEP induced a marked increase in accumulation of both ADR and NK-2280 in the ADR-resistant strains of EAT cells. The increase in ADR accumulation by hyperthermia and CEP is possibly due to an increase in the cell membrane potential and the inhibition of ADR efflux by CEP respectively. In the wild strain of EAT cells, we also evaluated the effect of extracellular pH change on ADR accumulation and the cell membrane potential and their alteration by hyperthermia and CEP. ADR accumulation decreased as pH decreased, but the cell membrane potential was not appreciably affected by pH change so far examined. Hyperthermia alone or combined with CEP significantly increased ADR accumulation in a pH range from 6.2 to 7.6. Hyperthermia increased the accumulation of ADR in the tumour cells, although its pH dependency was not completely resolved. CEP enhanced ADR accumulation more markedly in ADR-resistant cells than in wild-type cells. Therefore, the combination of hyperthermia and CEP may be very effective to increase the ADR cytotoxicity to ADR-resistant tumours.

External capacitive heating is the usual method of electromagnetic wave heating, in which the tumor is caught and heated between two opposite applicators. Using a phantom, the authors developed and evaluated the performance of a new capacitive heating applicator designed for simultaneous radiohyperthermotherapy (SRH) in which the electron beam irradiation is provided from above an external capacitive heating applicator for the treatment of superficial and shallow-seated tumors. The trial applicator was constructed to fulfill the following conditions: 1. use of an electrode plate which does not affect the electron beam depth dose, 2. a uniform thickness to maintain flatness of the electron beam, and 3. a cooling function to prevent damage to normal skin tissue and enhance the therapeutic gain factor. This applicator was comprised of a 0.1-mm-thick copper electrode and a 5-mm-thick cooling chamber. The depth of the 80% dose of the new applicator was 21 mm with a 9-MeV electron beam and 36mm with a 15-MeV electron beam, which was comparable to the effect of a conventional irradiation bolus. The temperature distribution produced by the trial applicator was symmetrical on both sides from the center of the applicator. The 50% specific absorption rate region was 6.4 cm wide at a depth of 1 cm from the phantom surface and 2.8 cm wide at a depth of 3 cm. There have been no previous reports on the development of an external capacitive heating applicator designed for the SRH of superficial and shallow-seated tumors; this is the first such report.(ABSTRACT TRUNCATED AT 250 WORDS)

Simultaneous radiohyperthermotherapy (SRH) is a combined hyperthermia-radiation therapy in which irradiation is given during heating. Mutual interference between the high energy radiotherapy system (Toshiba LMR-15A) and the 13.56 MHz capacitive heating system (Omron HEH-500C) was tested with phantom materials prior to a clinical trial with SRH. The energy and flatness of irradiation were not affected by the heating system within the range of clinical use. The high energy radiotherapy system did not affect the increase or distribution of temperature during simultaneous treatment. The results of this phantom study indicated that these apparatuses would not produce clinically significant mutual interference during SRH. A clinical trial was performed on a 57-year-old woman with postoperative recurrence of rectal cancer. This is the first reported clinical case treated with true SRH in which external irradiation was administered during mid capacitive heating. Twelve SRH treatments were performed on the recurrent lesion at a frequency of twice a week for six weeks using the apparatuses described above. There was a significant reduction in pain after treatment. The tumor marker carcinoembryonic antigen (CEA) level decreased after treatment. On CT images taken after treatment, the tumor site became a low density area which indicated necrosis. There were no side effects. These results suggest that further clinical study of SRH should be performed to clarify its advantages.