Radiofrequency capacitive hyperthermia for deep-seated tumors. II. Effects of thermoradiotherapy

Clinical effects and safety of radiofrequency (RF) capacitive hyperthermia in combination with radiotherapy were evaluated in 40 patients with locally advanced deep-seated tumors. Hyperthermia was administered regionally with an 8-MHz or a 13.56-MHz RF heating device, once or twice a week after irradiation, four to 13 sessions total. Radiotherapy was delivered in fractions of 170 to 200 cGy a day, 5 days a week to 30 to 70 Gy to 33 patients, whereas the remaining seven patients received a total dose of 28 to 60 Gy in fractions of 400 cGy, twice a week. Six of the 40 tumors treated showed CR (100% regression), 6 PRa (80%-100% regression), 13 PRb (50%-80% regression), and 15 NR (less than 50% regression) when assessed by tumor size on computerized tomography (CT) scan. The tumor size before treatment was significantly smaller in CR + PRa tumors than in PRb + NR ones. TDF Time-dose fractionation (TDF) and number of heat treatments, however, did not differ significantly between the both tumors. Greater regression was observed in tumors heated to 41 to 43 degrees C in the maximum temperature than in tumors heated to below 41 degrees C or above 43 degrees C. The minimum tumor temperature was not related to the tumor regression. Posttreatment CT scan revealed remarkable low-density areas in 18 of the 34 tumors that did not regress completely. Histopathologic examinations demonstrated the low-density area to be massive coagulation necrosis and no malignant cell was observed in two tumors examined thoroughly. The types of low-density areas, which were classified according to its percent area in the tumor, correlated with the maximum and minimum tumor temperature. Most of the type III tumors (more than 80% low density) did not regrow in follow-up studies. Complications consisted of subcutaneous fat necrosis in four patients, local edema in four patients, and one abdominal abscess in one patient, all of which eventually resolved. These clinical results strongly suggest the usefulness of RF capacitive hyperthermia combined with radiotherapy for the treatment of refractory deep-seated tumors, and that intratumor low-density areas which appear on posttreatment CT seems to be a good parameter for assessing the tumor response to thermoradiotherapy.     

Regional hyperthermia combined with radiotherapy in the treatment of lung cancers.

Twenty locally advanced lung cancers were treated by hyperthermia in combination with radiotherapy between November 1980 and January 1990. All tumors selected had invaded or were in contact with the chest wall, so that transcutaneous insertion of thermal probes into the tumor was possible. Using an 8 or 13.56 MHZ RF capacitive heating device, hyperthermia was given once or twice a week after irradiation for 30-60 min per session (1-12 sessions in total). Radiotherapy was delivered at dose of 13.6-70 Gy. The thermal parameters analyzed were a) maximum, average, and minimum intratumor temperatures (Tmax, Tav, and Tmin), which were recorded at the termination of each treatment, and b) the percentages of the intratumor points that exceeded 41 C (%T greater than or equal to 41 C). The mean +/- SD for Tmax, Tav, Tmin, and %T greater than or equal to 41 C was 42.9 +/- 1.7 C, 41.6 +/- 1.2 C, 39.7 +/- 1.1 C, and 56.2 +/- 25.8, respectively. Larger tumors showed higher thermal parameters than the smaller tumors. Of the 12 tumors treated by definitive therapy, 2 (17%) achieved CR, 7 (58%) PR, and 3 (25%) NR. Four of 10 tumors that did not achieve CR showed large intratumor low density areas on post-treatment CT, reflecting massive coagulation necrosis. Higher thermal parameters were closely related to the appearance of low-density areas but not to changes in tumor size. Four tumors treated preoperatively were successfully resected 2 weeks after thermoradiotherapy, whereas four palliatively-treated tumors showed no regression. The side effects associated with hyperthermia were pain in 12 patients (60%) and dyspnea in 3 (15%), all of which resolved after termination of treatment. A skin abscess and a pneumothorax attributed to thermal probe insertion were observed in one patient each. These results indicate that regional RF capacitive hyperthermia is clinically feasible for local treatment of selected lung cancers.     

Interstitial thermoradiotherapy: thermal dosimetry and clinical results

From August 1977 to August 1986, 72 patients with advanced primary or recurrent cancers were treated using interstitial thermoradiotherapy. Sites treated included the pelvis in 49 patients, the head and neck in 15, and other sites in six. Median tumor volume was 52 cm3, and all but nine patients had received prior irradiation. In 69 patients, hollow stainless steel catheters were implanted and used as electrodes with a 0.5 MHz radiofrequency (RF) generator, whereas in three patients, standard plastic Henschke tubes were used with a commercially available interstitial microwave (MW) system operating at 915 MHz. Most patients were heated intraoperatively for 30 minutes, aiming for a minimum measured intratumoral temperature (Tmin) of 42 degrees C. The implant was occasionally preceded by external irradiation, and after hyperthermia, the catheters were afterloaded with 192Ir for brachytherapy. Tmin exceeded 42 degrees, 42.5 degrees, 43 degrees, and 44 degrees in 25, 16, 12, and 3, respectively, of 70 patients with temperature data available, and the probability of successful heating was independent of tumor volume or site. Twenty-five of 69 (36%) evaluable patients achieved a complete response (CR). Probability of CR demonstrated a significant univariate dependence upon Tmin, radiation dose, site treated, and tumor volume, but multivariate analysis showed only three significant predictor variables: tumor volume, radiation dose, and Tmin. The probability of a CR ranged from 95% for patients with small tumors receiving high doses of radiation and adequate heat, to 5% for patients with large tumors receiving low radiation doses and less than adequate heat. Of 25 patients with CR, 10 relapsed; median response duration was less than 18 months, depended marginally upon disease site, and was independent of Tmin, radiation dose, and tumor volume. Seventeen patients sustained a complication, of which nine were severe enough to require hospitalization or surgery. All severe complications occurred in patients with pelvic tumors. The probability of a complication of any severity had a significant univariate association with maximum intratumoral temperature (Tmax) and tumor size. We conclude that interstitial thermoradiotherapy offers the promise of heating large tumors in locations where externally applied hyperthermia has not been successful.     

Initial clinical results of a 430 MHz microwave hyperthermia system using a lens applicator

The applicability of a 430 MHz microwave (MW) hyperthermia system using an electric field converging (lens) applicator was evaluated. Twenty-two tumors with a maximum tumor depth of less than 7 cm (10 chest wall tumors, 8 abdominal and pelvic tumors, 2 extremity tumors, and 2 neck tumors) were treated with the lens applicator heating system for a total of 72 sessions in conjunction with irradiation or chemotherapy. Of the 72 heat sessions, our treatment goal of 30 min of hyperthermia with all monitored tumor temperatures above 42 degrees C was achieved in 31 sessions (43%). The average tumor temperature was 42.5, 43.1, 42.0, and 42.0 degrees C for chest wall, abdominal and pelvic, extremity, and neck tumors, respectively; similarly 88, 83, 64 and 50% of monitored points exceeded 41 degrees C. A lens applicator heating system increased the penetration depth of MW, and tumor temperature of 41 degrees C at 5 cm from the surface was easily achieved with a four-aperture lens applicator. Of the 22 tumors, 10 tumors exhibited complete response (CR), 7 partial response (PR) and 5 no response (NR). These results suggest that the lens applicator heating system is useful for heating localized subsurface tumors with a maximum tumor depth of 5-6 cm.     

Clinical research on hyperthermia of cancer using microwave heating equipment of lens applicator type

Ninety cases with 96 tumors were treated by the 430 MHz microwave heating systems, HTS-100, at Tokyo Metropolitan Komagome Hospital, Kyoto University and Aichi Cancer Center. The results of treatment were analyzed, and the following have been clarified. Three cases are demonstrated showing feature of HTS-100. 1) The results of 383 sessions of heating by HTS-100 were analyzed, and it has been clarified that even the larger tumors, more than 5 cm both in size and depth, can be heated satisfactorily to temperatures higher than 42 degrees C. This system is capable of heating remarkably wider areas compared with the conventional microwave heating systems. 2) Hyperthermia by HTS-100 and radiotherapy were combined for treatment. The success rate (total percentage of CR plus PRa) of 89 cases analyzed was as high as 66.3%. Furthermore, local heating was successful for 60.7% of tumors, larger than 5 cm and deeper than 4 cm. 3) Combination of microwave heating and RF wave heating is a new method which is helpful for expansion of indications. 4) The frequencies of side effects of HTS-100 heating were: pain, 15.6%; sensation of heat, 6.3%; burns, 3.6%. Most of side effects were transient and slight. The higher frequency of pain than the conventional microwave heating is attributable to expansion of heating area.     

Clinical results of loco-regional hyperthermia combined with chemotherapy in the treatment of malignant tumors

From December 1982 through January 1989, 22 patients with 25 tumors were treated by thermochemotherapy. Of the 25 tumors, 13 were locally recurrent tumors after radiotherapy, 10 distant metastases, and 2 peritoneal disseminations. Employing two types of heating devices (8MHz capacitive RF, 430MHz microwave), hyperthermia was administered once or twice weekly, for 30-60 minutes per session, up to total sessions of 2-15 (mean = 6.9). In some sessions, anticancer drugs were administered intravenously or intraarterially immediately before or simultaneously with hyperthermia. Of the 25 tumors treated, 2 (8%) showed CR, 11 (44%) PR, 7 (28%) NC, and 5 (20%) PD. The better the tumor response was, the higher local control rate was achieved. The survival rate of patients who achieved CR or PR was higher than that of patients who showed NC or PD. Tumor volume, depth of tumor, averaged maximum intratumor temperature, the number of effective heat sessions and the number of anticancer drugs used were shown to affect the tumor response by multivariate analysis. On the other hand, averaged minimum intratumor temperature and history of previous treatment did not affect the tumor response. As almost all the tumors treated were considered to be refractory to radiotherapy or chemotherapy, the tumor responses obtained with thermochemotherapy seemed very encouraging. The expanded trials are warranted to reveal the effectiveness of thermochemotherapy.     

Hyperthermia alone in the treatment of recurrences of malignant tumors. Experience with 60 lesions

Localized hyperthermia alone has been used for the treatment of cancer recurrences in which previous conventional therapies have failed. Since 1983 and 1988, 57 patients with 60 lesions have been heated by means of a microwave and radiofrequency system. Treatment protocol provided 45 minutes of heating at the intratumor temperature of at least 42 degrees C, twice a week, for a total number of six, eight, or ten heating sessions. Invasive intratumor thermometry was performed for all lesions. Complete response (CR) was obtained in ten cases (16.6%) and partial response (PR) in 14 (23.4%). Higher rates of CR were observed in the chest wall (38.5%) compared with the head and neck area (11.4%), trunk (10%), and limbs (none). Adenocarcinoma was the most responsive histologic type (40%). Squamous cells carcinoma had 7.7% CR. The only case of undifferentiated carcinoma showed CR; there were none on five sarcomas. Long-term local control (24 months) was approximately 7%. The multivariate analysis showed the statistical significance of the histologic variety (adenocarcinoma versus others, P less than 0.0001). Side effects and complications of the treatment were minimal.     

Relationship between vascular thermotolerance and intratumor pH.

The changes in blood flow, intratumor pH, and clonogenicity of tumor cells after one and two heatings were studied in SCK tumors of A/J mice. When SCK tumors were heated at 42.5 degrees C for 1 hr, vascular thermotolerance promptly developed and peaked at 18 hr post-heating. The intratumor pH was 7.05 +/- 0.14 (mean +/- S.D.) in control SCK tumors of A/J mice, with a significant decrease (p less than or equal to 0.001) to 6.86 +/- 0.08 and 6.70 +/- 0.08 when heated for 1 hr at 43.5 degrees C and 44.5 degrees C, respectively. However, when the vascular thermotolerance was at its peak, heating at the same doses caused little change in the intratumor pH. When SCK tumors were heated for the first time at 44.5 degrees C for 1 hr and left in situ, the number of clonogenic cells significantly declined. Such a secondary cell death could be attributed to the deterioration of the intratumor environment ensuing from the vascular damage. When the tumor vessels were thermotolerant, however, virtually no secondary cell death occurred after heating.     

Hyperthermia combined with radiation therapy for primarily unresectable and recurrent colorectal cancer.

The value of adjuvant hyperthermia to radiotherapy in the treatment of locally advanced colorectal cancers was investigated. Between 1981 and 1989, 71 primarily unresectable or recurrent colorectal tumors were treated with radiotherapy at the Department of Radiology, Kyoto University Hospital. Of the 71 tumors, 35 were treated with radiotherapy plus hyperthermia (group I), while 36 tumors (group II) were unsuitable for hyperthermia mainly because of difficulties with the insertion of temperature probes or the thickness of the patient's subcutaneous fat (greater than 2 cm). The mean total radiation dose was 58 Gy and 57 Gy for groups I and II, respectively. Thirty deep-seated pelvic tumors were treated with an 8 MHz radiofrequency capacitive heating device, and five subsurface tumors were treated with a 430 MHz microwave hyperthermia system. Hyperthermia was given following radiotherapy for 30-60 min for a total of 2-14 sessions (mean 5.7). In 32 of the 35 tumors heated, direct measurement of tumor temperature was performed. For the five tumors treated with the microwave heating device, the means of the mean maximum, average, and minimum measured intratumoral temperatures were 45.4 degrees C, 43.3 degrees C, and 40.6 degrees C, respectively. The corresponding values were 42.2 degrees C, 41.3 degrees C, and 40.3 degrees C for the 27 tumors treated with the capacitive heating device. Effective heating of deep-seated pelvic tumors was more difficult than heating of abdominal wall or perineal tumors. The local control rate at 6 months after the treatment, which was defined as absence of local progression of the tumors, was 59% (17/29) and 37% (11/30) for groups I and II, respectively. The objective tumor response rate (complete regression plus partial response) evaluated by computed tomography was 54% (19/35) in group I, whereas it was 36% (10/28) in group II. A better response rate of 67% was obtained in the 15 tumors with a mean average tumor temperature of greater than 42 degrees C. Although limitation of our current heating devices exist, the combination of hyperthermia with radiotherapy is a promising treatment modality in the treatment of locally advanced colorectal cancer.     

Hyperthermia and radiation in vivo: effect of 2-deoxy-D-glucose

Since hypoxic cells rely heavily on glucose metabolism for energy, 2-deoxy-D-glucose (2-DG), an inhibitor of anaerobic glycolysis, would be expected to increase tumor cell killing by heat and thus enhance the effect of concurrent radiation. In order to test this hypothesis two types of BALB/c mouse tumors, one induced by subcutaneous injection of 10(6) herpes virus Type 2-transformed (H238) cells and the other by injection of 1.6 X 10(5) 1,2-dimethylhydrazine-transformed (#51) cells in the right thigh, were subjected to radiation, 2-DG, and heat used singly and in various combinations. Control mice were injected with saline. Three to four weeks after inoculation the mice were assigned to one of eight treatment groups (28 mice/group) so that average tumor volume/group before treatment would be equivalent. A single 2000 rad dose of radiation 3 hr prior to heat and 2-DG injected intraperitoneally at 1 g/kg 30 min before heating were given to some of the groups. Localized heat at 43.5 +/- 0.1 degrees C for 30 min, when used, was administered by means of a water bath. Rectal temperatures were kept below 39 degrees C, whereas intratumor temperatures reached a maximum of 42 degrees C. After treatment, tumor volume, mouse weight, and mortality were noted twice a week for four weeks. In both tumor models, mice receiving radiation plus heat, and radiation plus heat plus 2-DG, had significantly smaller tumors over the entire 4 to 28 day range after treatment than saline-injected control mice. In addition, in the H238 tumor model, addition of 2-DG to treatment with radiation and heat resulted in significantly smaller tumors at 25 days. 2-DG alone or in combination with heat (without radiation) resulted in significantly smaller H238 cell-induced tumors at day 28 post-treatment when compared to the saline controls. The H238 tumor-bearing mice experienced a significant (4.7%) loss in total body weight after heating. It could be that heating trauma produced dehydration and possibly also decreased caloric intake to an extent which could be measured in weight loss. This observation, however, was not made in the heated mice in the #51 tumor model.     

Randomized phase III study comparing irradiation and hyperthermia with irradiation alone in superficial measurable tumors. Final report by the Radiation Therapy Oncology Group

A total of 307 patients with superficial measurable tumors were registered on a Radiation Therapy Oncology Group (RTOG) protocol involving fractionated radiation therapy, either alone or followed immediately by hyperthermia (42.5 degrees C, 45-60 min). Overall complete response (CR) was observed in 30% of the lesions treated with radiotherapy (RT) and 32% of those receiving RT and heat. Response was found to be significantly related to both maximum tumor diameter (less than 3 or greater than or equal to 3 cm) and site/histology (breast/adenocarcinoma, head and neck/squamous, or other site/histologies). In tumors less than 3 cm in diameter in the breast, trunk, and extremities, a better CR rate was noted with irradiation and heat (62 and 67%) than with irradiation alone (40 and 0%). However, in the head and neck there was only minimal difference in CR with irradiation alone or combined with hyperthermia (50 vs 38%). In lesions less than 3 cm treated with irradiation and heat, there was improved local control. In lesions greater than 3 cm, there was no difference in local control between the two treatment arms. The higher response rate in patients with smaller lesions (less than 3 cm) may be explained by the fact that these tumors are easier to heat. Problems in correlating tumor response with quality of heating include less than optimal heating in larger lesions and the limited ability of current thermometry to map the temperature distribution in a tumor. Acute and late toxicities in both treatment arms were comparable, except for an overall 30% incidence of thermal blisters in the heated tumors.     

Quality assurance problems in clinical hyperthermia and their impact on therapeutic outcome: a Report by the Radiation Therapy Oncology Group

Since February 1981, 300 patients with superficial measurable tumors were randomized on an RTOG protocol (81-04) involving fractionated radiation therapy (4.00 Gy twice weekly for a total of 32.00 Gy), either alone or followed immediately by hyperthermia (42.5 degrees C, 60 min). This is a report of 218 eligible patients with single lesions: 107 treated with radiotherapy alone (RT), 111 with radiotherapy plus hyperthermia (RT + HT). Only 56% of the 24 tumors less than 3 cm and 36% of the 53 lesions larger than 3 cm received what was felt to be "adequate" therapy (greater than or equal to 29 Gy and 8 heating sessions). Overall complete response (CR) was observed in 28% of the patients treated with RT, and 32% of the patients receiving RT and heat. Response has been found in previous analyses of this and other RTOG studies to be significantly related to both maximum tumor diameter (less than 3 or greater than or equal to 3 cm) and site/histology (breast/adenocarcinoma, head and neck/squamous, or other site/histologies). In the head and neck tumors less than 3 cm in diameter there was no difference in CR with irradiation alone or combined with hyperthermia (46% vs 43%). However, in the breast, and trunk and extremities a better CR rate was noted with irradiation and heat (55% and 67%) than with irradiation alone (33% and 0). In lesions less than 3 cm treated with irradiation and heat the probability of remaining in response was 80% compared with 15% with irradiation alone. In lesions larger than 3 cm no difference in CR was observed in either treatment group. It has been hypothesized that the response rate is higher in patients with smaller lesions (less than 3 cm) and in breast/chest wall, trunk/extremity lesions because these tumors and anatomical sites are easier to heat adequately. Problems encountered in correlating tumor response with quality of heating include less than optimal heating in larger lesions and the limited ability of current thermometry to accurately represent the temperature distribution in a tumor. Furthermore, differences in equipment and treatment practices among institutions add to the variability in heat administration data collected. In addition, tumor response may be difficult to judge because of short survival of some patients and occasionally rapid tumor regression that may cause necrosis which may be misinterpreted as persistent tumor.(ABSTRACT TRUNCATED AT 400 WORDS)     

Changes in intratumor pH by two heatings

It is a known fact that pH in rodent tumors decline significantly upon heating most likely due to breakdown of the tumor blood circulation. We recently observed that tumor blood vessels become thermotolerant after being heated with a sublethal thermal dose. The purpose of the present study was to reveal whether heating can reduce intratumor pH when the tumor vessels are thermotolerant. When the SCK tumors of A/J mice were heated at 42.5 degrees C for 1 h, the tumor vessels became most thermotolerant at 18 h postheating, as measured with the 86Rb uptake method. The intratumor pH in the control SCK tumors was 7.05 +/- 0.14 (SD), and it significantly decreased to 6.70 +/- 0.08 (P less than 0.001) after heating at 44.5 degrees C for 1 h. However, when the tumor vessels were thermotolerant, i.e., 18 h after heating at 42.5 degrees C for 1 h, reheating at 44.5 degrees C for 1 h could not reduce the intratumor pH. We concluded that such a failure to increase tumor acidity by a second heating at temperatures as high as 44.5 degrees C was due to vascular thermotolerance developed by the first heating.     

Response of canine oral carcinomas to heat and radiation

Thermal enhancement of radiation response improved the probability for local tumor control without increasing the risk for late complications in this study of relatively advanced stage tumors. Thirty-eight dogs with naturally occurring oral carcinomas were randomized to two radiation dose response groups to receive radiation alone or combined with local hyperthermia. Radiation was delivered in 10 fractions over 22 days. Heating was done 3 hours after seven of the radiation doses. The objective was to maintain a minimum tumor temperature of 42 degrees C and a maximum normal tissue temperature of 40 degrees C for 30 minutes. Normal tissue temperatures were usually 40 degrees C or less but there was great heterogeneity in tumor temperatures. Temperatures at tumor margins never exceeded 41.5 degrees C. The TCD50 for radiation was 38 Gy (32-46 Gy, 95% C.I.) and for radiation and heat it was 33 Gy (30-36 Gy, 95% C.I.). The slope of the dose response was much steeper for radiation and heat than for radiation alone indicating that the heterogeneity of tumor response was decreased with heat. All tumors were controlled at 40 and 45 Gy with heat whereas only 57% and 75% were controlled with 40 and 45 Gy radiation only. There were no late necroses for radiation and heat. The tumor control enhancement might be improved with different sequences, number of heatings or other time temperature relationships. It is not possible to predict the optimum treatment scheme because of the lack of knowledge of the influence of hyperthermia on subsequent heat or radiation treatments. That influence could be affected greatly by changes in tumor microcirculation, pH, and oxygenation as well as development and decay of thermotolerance in tumor and normal tissue.     

Enhanced thermal response of a rat sarcoma by Corynebacterium parvum

Corynebacterium parvum was investigated in the response of rat Mc7 sarcoma to local waterbath hyperthermia. Heat treatment of 1-1.5 cm3 foot tumors at 43 degrees C for 2 h resulted in complete regression of 71% of the tumors. The Mc7 cure was reduced to 31% when the tumors were heated at 43 degrees C for 1.5 h. C. parvum (700 micrograms, i.v.) when given 1-3 days before tumor heating at 43 degrees C for 1.5 h increased the host phagocytic activity, and the tumor regression from 31% to 65% (P less than 0.05). C. parvum by itself had no curative effect on the tumor, and it did not enhance the thermal response of normal rat foot to hyperthermia. These findings suggest that host response to tumor heating may be 'non-specific' in nature involving phagocytes of the reticulo-endothelial system.     

Combined treatment with radiation and hyperthermia in metastatic malignant melanoma

In 24 patients with metastatic malignant melanoma, combined treatment with radiation and hyperthermia was administered to 38 localizations, radiation alone to 8 comparative localizations and hyperthermia alone to 3 localizations. Hyperthermia was administered during one hour by using a 433 MHz microwave generator. The heat treatment was given within 30 min following irradiation. Although an intratumoral temperature of 43 degrees C was aimed, considerable variations occurred during one session and from session-to-session. Radiation schedules consisted in either one large fraction (6-8 Gy) once a week in 14-21 days or two fractions (4-5 Gy) twice a week in 21 days. In the group of patients receiving irradiation once a week, three heat treatments were administered. In the twice-a-week radiation schedule, six heat sessions were given. The overall complete response (CR) rate in patients receiving combined treatment was 50%. In the group of patients treated with hyperthermia and irradiation schedules of 8 Gy per fraction, the CR rate was 83%. Irradiation alone achieved 38% CR rate but some of these CR relapsed during follow-up whereas the comparative area treated with radiation and heat remained under control at this time. The lesions treated with heat alone did not show any response to treatment. Enhancement of the acute skin reactions was generally observed. However, because the total doses were relatively low, this enhancement did not constitute a clinical problem. CR appears to occur more frequently in small tumor sizes. The highest and lowest temperature ever registered during any session of hyperthermia did not seem to correlate with the tumor response.     

Preliminary results of a phase III trial of spontaneous animal tumors to heat and/or radiation: early normal tissue response and tumor volume influence on initial response

A Phase III randomized trial was initiated to test the relative efficacies of heat alone, radiation alone and heat plus radiation using spontaneous malignancies in pet animals. Heat alone was inferior to the other two treatment arms as demonstrated by a significantly higher non-response rate and shorter response duration. The ratio of complete response rates (CR) for heat plus radiation to radiation alone or the thermal relative risk (TRR) was greater for tumors greater than 10 cm3 as compared to those less than 10 cm3 (TRR = 4.8 and 1.4, respectively). The overall TRR for complete responses was 2.3. The CR data for the combined therapy arm indicate at least an additive effect between heat and radiation for small tumors but most likely a synergistic effect in the larger tumor group. Based on the data currently available, no significant difference in response duration is observed between the two radiation arms, although a nonsignificant advantage to the combination therapy exists. Normal tissue effects were evaluated by incidence of full moist desquamation within the irradiated volume, late fibrosis and bone necrosis. Since the radiation skin dose depended upon the technique being used it was possible to estimate the dose to achieve moist desquamation in 50% of the animals (DD50) by a logistic regression model as being 3728 +/- 344 rad for radiation alone. Significant lowering of the DD50 was not observed for the addition of heat to radiation. Low patient numbers where intact skin was heated prevented an accurate analysis of the effect, however.     

Radiofrequency thermotherapy for malignant liver tumors

Inoperable malignant liver tumors have been treated by radiofrequency hyperthermia at Kyoto University Hospital since 1983. In this study, clinical hyperthermia for malignant liver tumor was evaluated for 67 tumors in which we could measure intratumor temperatures. Of the 67 tumors, 41 were hepatocellular carcinomas (HCC), six cholangiocarcinomas, and 20 metastatic tumors. Cholangiocarcinoma and metastatic tumors were more susceptible to this treatment than HCC. Of the three types of HCC, higher intratumor temperatures were achieved in the diffuse type than in the nodular or massive types. The minimum tumor temperature of HCC stayed below 40 degrees C in 46% of cases, especially in larger tumors. The local response rates (complete remission plus partial remission/all) were 28% and 11% for HCC and non-HCC, respectively, for thermochemotherapy; 86% and 33%, for thermoradiotherapy; and 33% and 89%, for thermotherapy with embolization. No apparent relationship was observed between the intratumor temperatures and local response rate.     

Radiofrequency capacitive hyperthermia for deep-seated tumors. I. Studies on thermometry

The thermometry results of radiofrequency (RF) capacitive hyperthermia for 60 deep-seated tumors in 59 patients are reported. Hyperthermia was administered regionally using two RF capacitive heating equipments which the authors have developed in cooperation with Yamamoto Vinyter Company Ltd., (Osaka, Japan). Intratumor temperatures were measured by thermocouples inserted through angiocatheters which were placed 5 cm to 12 cm deep into the tissues. Tumor center temperatures were measured for 307 treatments in all tumors; thermal distributions within tumors and surrounding normal tissues were obtained for 266 treatments of 53 tumors by microthermocouples. Thermometry results obtained were summarized as follows. A maximum tumor center temperature greater than 43 degrees C and 42 degrees C to 43 degrees C was obtained in 23 (38%) and 14 (23%) of the 60 tumors respectively. The time required to reach 43 degrees C in the tumor center was within 20 minutes after the start of hyperthermia in 87% of tumors heated to more than 43 degrees C. Temperature variations within a tumor exceeded 2 degrees C in 81% of tumors heated to more than 43 degrees C. The lowest tumor temperature greater than 42 degrees C was achieved in six of the 53 tumors (11%). Of 42 tumors in which temperatures of the subcutaneous fat, surrounding normal tissues, and the tumor center were compared, 24 (57%) showed the highest temperature in the tumor center and ten (24%) in the subcutaneous fat. When the heating efficacy was assessed in terms of a maximum tumor center, it great deal depended on the treatment site, tumor size, thickness of subcutaneous fat, and tumor type. Tumors in the head and neck, thorax, lower abdomen, and pelvis could be heated better than tumors in the upper abdomen. Greater heating efficacy was shown in patients with large, hypovascular tumors, and with the subcutaneous fat measuring less than 15 mm thick. The predominant limiting factor for power elevation was pain associated with heating. Systemic signs including increases in pulse rate and body temperature were not serious and seldom became limiting factors for power elevation. Our thermometry results indicate that the advantages of deep RF capacitive heating are its applicability to various anatomic sites and negligible systemic effects. The disadvantages are that its primary usefulness is limited to patients with thin subcutaneous fat and with large or hypovascular tumors.     

Multi-institutional studies on hyperthermia using an 8-MHz radiofrequency capacitive heating device (Thermotron RF-8) in combination with radiation for cancer therapy

A joint clinical trial of hyperthermia using a newly developed 8-MHz radiofrequency (RF) capacitive heating device (Thermotron RF-8; developed in cooperation with Yamamoto Vinyter Co. of Osaka) was performed under collaboration of seven institutions. Radiation with 4 Gy twice a week for a total of 40 Gy or 2 Gy five times a week for a total of 50 Gy was delivered. After irradiation, hyperthermia at 42.5 degrees C +/- 0.5 degree C for 40 to 60 minutes was given twice a week for a total of 10 times. Tumors examined in this trial were located in various depths in the body, and included those which were considered refractory to conventional treatments or radioresistant such as malignant melanoma and soft tissue tumors. Of the 63 tumors treated, 52.4% showed complete regression (CR); 19.0% more than 80% regression (PRa); 20.6%, 80% to 50% regression (PRb); and 8.0% no regression (NR). Our joint clinical trial demonstrated that hyperthermia with the use of the Thermotron RF-8 is safe and effective in the treatment of radioresistant tumors located in superficial, subsurface, and in some cases deep regions, if the surface cooling is properly managed by the temperature-controlled saline pad and electrodes of appropriate size are paired.