PURPOSE: To assess the efficacy of radiotherapy (RT) combined with regional hyperthermia (HT) guided by radiofrequency (RF)-output power and intraesophageal temperature and evaluate the potential contribution of HT to clinical outcomes in patients with Stage III non-small-cell lung cancer (NSCLC).

METHODS AND MATERIALS: Thirty-five patients with Stage III NSCLC treated with RT plus regional HT were retrospectively analyzed. Twenty-two of the 35 patients underwent intraesophageal temperature measurements. Patients with subcutaneous fat of 2.5 cm or greater, older age, or other serious complications did not undergo this therapy. The 8-MHz RF-capacitive heating device was applied, and in all patients, both the upper and lower electrodes were 30 cm in diameter, placed on opposite sides of the whole thoracic region, and treatment posture was the prone position. The HT was applied within 15 minutes after RT once or twice a week.

RESULTS: All thermal parameters, minimum, maximum, and mean of the four intraesophageal temperature measurements at the end of each session and the proportion of the time during which at least one of the four intraesophageal measurements was 41 degrees C or higher in the total period of each session of HT, of the intraesophageal temperature significantly correlated with median RF-output power. Median RF-output power (>/=1,200 W) was a statistically significant prognostic factor for overall, local recurrence-free, and distant metastasis-free survival.

CONCLUSIONS: The RT combined with regional HT using a higher RF-output power could contribute to better clinical outcomes in patients with Stage III NSCLC. The RF-output power thus may be used as a promising parameter to assess the treatment of deep regional HT if deep heating using this device is performed with the same size electrodes and in the same body posture.

Hyperthermia (HT) can be directly cytotoxic to cancer cells, and can also act as a radiation-sensitizer and chemo-sensitizer. Although the combination of HT with radiotherapy has been the primary focus for research, there is an equally strong rationale for combining HT with chemotherapy (CT). New chemotherapeutic agents, such as irinotecan, oxaliplatin, gemcitabine and taxane, have been demonstrated to show thermal enhancement in several in vitro and/or in vivo studies. With regional or local HT, drug- and heat-induced toxicity can be localized and systemic toxicity can be avoided or minimized. Generally, regional HT is less invasive than interstitial or intracavitary local HT and can enhance chemotherapeutic effects in specific sites in the body. In many instances, systemic CT represents the most useful option for patients with surgically incurable malignant neoplasms. An approach which combines systemic CT with regional HT should be of interest, since it can enhance the efficacy of systemic chemotherapeutic drugs in specific areas. Here, we review clinical results of systemic CT combined with regional HT for the treatment of malignant neoplasms.

Most patients treated with hyperthermia have tumors which are refractory advanced and/or recurrent tumors which cannot be controlled by conventional treatments, and their performance status is often poor. Thus, it is very difficult for these patients to maintain a physical position suitable for heating tumors whose temperatures can be maintained at more than 42°C for nearly an hour (in order to induce direct toxicity in tumor cells). Furthermore, we sometimes cannot help interrupting the heating due to acute adverse reactions such as severe pain. In addition, it is also very difficult to heat tumors homogeneously to temperatures over 42°C, using currently available heating devices. In many clinical studies in which hyperthermia was used to enhance the efficacy of radiotherapy, tumor temperatures could be increased only to the 40-41.5°C range. Under these conditions, heat-induced cell death, increased cellular radiosensitivity, and vascular damage are likely to be insignificant in spite of the increased response of tumors to radiotherapy. Recently, mild temperature hyperthermia (MTH)-induced physiological effects on tumors have been shown to lead to an increased blood flow and a resulting increase in tumor oxygenation, and this could lead to increased radiosensitivity if radiotherapy was used after MTH, and to an increase in chemosensitivity via an increased transport of drugs into tumors. Therefore, if the clinician's goal is to keep the tumor temperature in the 40-4tC range, it is possible to reduce a patient's burden, make it easier to maintain a patient in a suitable position for heating, and avoid interrupting the heating session. In thermo radiotherapy, when heating at temperatures higher than 42-43°C can be warranted, hyperthermia should be performed after radiotherapy. However, when heating over 42°C is difficult, an alternative useful approach may be to reverse he order of radiotherapy and hyperthermia: specifically apply radiotherapy subsequent to tumor oxygenation-inducing MTH.

Clinical research in hyperthermic oncology began in 1978, when the research group chaired by Prof. T. Sugahara, supported by a grant from the Ministry of Education, played an important part. Six years later, the first annual meeting of the Japanese Society of Hyperthermic Oncology (JSHO) was held in Kyoto, and the 23rd meeting was held in Nara in 2006. Over this period, the number of members as well as the number of scientific papers presented has decreased. However, new technologies such as immuno-stimulation, high temperature ablation, and mild hyperthermia have been introduced into clinics. The health insurance control committee of the JSHO conducted a survey on the clinical applications of hyperthermia. Data obtained through the use of questionnaires have been used to present the state of hyperthermic treatment in the major hospitals in Japan. An outline of the patients and diseases treated with hyperthermia, heating conditions including combination therapy, and clinical outcomes were summarized in this study. From the viewpoint of fiscal responsibility at each hospital, the difference between income and expenses for hyperthermic therapy is something which cannot be ignored. Further analysis of survey data and additional survey studies might be essential to resolve this problem.

An 8-year-old girl was admitted to the hospital because of left hip and knee joint pain. We found a tumor in her left iliopsoas muscle, which was diagnosed as a synovial sarcoma. She received chemotherapy and radiotherapy at another hospital, but the tumor showed no response to the treatments. Metastatic humerus bone tumor developed, and she needed morphine derived analgesics. She was introduced to our hospital again, and we started hyperthermia treatment, after that her retroperitoneal tumor decreased in size. We have already performed hyperthermic therapy 27 times. She became not to ask for the analgetic drug and could go to school from her home. In this case, the significance of the treatment is that the tumor response was observed with hyperthermia alone.

Between 1990 and 1999, we performed radiohyperthermo-chemotherapy (RHC) in 4 patients with high-grade soft-tissue sarcomas of the limbs.
Methods: Radiotherapy involved the delivery of radiation at a dose of 2 Gy once daily on 16 days, to give a total dose of 32 Gy. Hyperthermia was conducted once a week, with a total of five sessions. Chemotherapy was performed by implanting a reservoir and administering cisplatin (3 mg/kg) three times, and pinorubin (an adriamycin derivative; 1 mgt kg) twice by intra-arterial infusion, at weekly intervals. These drugs were administered alternately during hyperthermia sessions.
Results: Tumor shrinkage was observed in 98 % (43/44) of the patients. Of the 36 patients with MO tumors, 30 were disease-free at final follow-up, 2 had no evidence of disease, 1 was alive with disease, and 3 had died of the disease. Amputation was required only in the first patient, and the affected limb was preserved in the other 43 patients. The surgical margin was wide in 9 patients and marginal in 29 patients, and intralesional excision was performed in 5 patients.
There was recurrence in only 1 of the 44 patients.

Local control of metastatic neck nodes is important for treatment in patients with locally advanced head and neck cancer. However, managing inoperable bulky metastatic nodes with necrotic tissue is difficult using ordinary chemo radiotherapy (CRT). Since, hyperthermia (HT) offers complementary and synergistic effects with irradiation and anti-cancer agents; HT combined with CRT was used for treatment in 11 patients with locally advanced head and neck cancer displaying bulky metastatic neck nodes. The 11 cases included 8 cases with pathological Complete Response (CR), 2 with Partial Response (PR) and 1 with No Change (NC). The response rate was 90.9%. Overall survival rate (OS) at 1 and 2 years was 90.9% and 42.4%, respectively, and median survival time was 22.0 months. Local control rate (LCR) was 61.4% at both 1 and 2 years. These clinical results indicate the effectiveness of thermo-chemo-radiotherapy in patients with head and neck cancer displaying bulky lymph node metastasis.

Fifty four-year-old patient with unresectable hypo pharyngeal cancer of T4N2cMO was treated with accelerated hyperfractionated radiotherapy (1.5Gy twice a day) and hyperthermia. Good tumor response was achieved by combined four sessions of hyperthermia with radiotherapy of 75Gy. Laryngopharyngectomy, cervical esophagectomy, and bilateral neck dissection were performed for re-growth of the primary site 2.5 months after thermo radiotherapy. There were no viable cells in all metastatic nodes; although scattered cancer nests were seen in the primary site. He has a local disease-free eleven months after resection.

We evaluated the effectiveness of radiotherapy combined with high-power hyperthermia with a radiofrequency output over 1500W for 13 patients with non-small cell lung cancer. An average total dose of 59.8 Gy by the conventional method, and an average of 12 sessions of hyperthermia during radiotherapy were employed. In addition, an average of 15 sessions of hyperthermia was administered after completing the radiotherapy. Complete response (CR, 100% regression) was achieved in 10/13 (77%) patients and partial response (PR, over 50% regression) in 3/13 (33%) for an overall response rate of 100%. Radiotherapy combined with high-power hyperthermia is especially advantageous for young patients with a thin subcutaneous fatty layer of the chest wall.

Purpose: Local control in lung cancer directly invading the bone is extremely poor. Effects of regional hyperthermia combined with conventional external beam radiation therapy were evaluated.

Materials and methods: Thirteen patients with non-small lung cancer (NSCLC) with direct bony invasion were treated with hyperthermia plus irradiation (hyperthermia group). The treatment outcome was compared with the historical treatment results in 13 patients treated with external radiation therapy alone (radiation alone group). In patients with no distant metastasis, radiation therapy at a total dose of 60--70 Gy was administered to both groups. Hyperthermia was performed for 45-60 min immediately after irradiation for two-four sessions with radio frequency capacitive heating devices.

Results: For primary response, 10 of the 13 tumors responded to the treatment (3 CR, 7 PR) in the hyperthermia group, whereas seven tumors responded (l CR, 6 PR) in the radiation alone group. The 2-year local recurrence-free survival rate for clinical Mo patients in the hyperthermia group and that in the radiation alone group were 76.1 and 16.9%, respectively. Three patients died of distant metastases within 2 years in the hyperthermia group, but two out of three tumors histologically disappeared, even in the autopsy examination. The 2-year overall survival rate for clinical Mo patients in the hyperthermia group and that in the radiation alone group were 44.4 and 15.40/0, respectively. No severe pulmonary complication was observed in either group.

Conclusions: Regional hyperthermia combined with conventional irradiation could be a tool to improve local control in patients with NSCLC deeply invading the chest wall.

As prognosis after radiotherapy for patients with unresectable intrathoracic tumors is still extremely poor, such patients need intensive treatment. The aim of this study is to investigate the feasibility of hyperthermia combined with chemotherapy or chemo-radiotherapy for patients with advanced intrathoracic tumors. Our treatment regimen consisted of weekly concurrent thermo-chemotherapy using a low-dose of CDDP and CPT-ll with or without definitive radiation therapy. Our study has demonstrated that 2 out of 11 tumors showed a complete response and partial response was achieved in 3 tumors as the initial effects of the treatment. Furthermore, 2 patients with advanced Pancoast tumors survived for over 2 years without any indication of recurrence. All patients underwent the complete course of treatment without evidence of grade 3 or worse non-hematological toxicity, including pneumonitis. We have therefore concluded that thermo-chemo-radiotherapy with concurrent administration of CDDP and CPT-II at a low dose may be tolerable and effective for unresectable intrathoracic malignant tumors.

Purpose: To improve the treatment results of locally advanced non-small cell lung cancer (NSCLC), we have been conducting a clinical trial using regional hyperthermia combined with radiotherapy.

Methods and Materials: Between 1985 and 1990, 19 patients were treated. All cases except one were regarded as initially unresectable. There were 10 Stage IlIA cases and nine Stage HIB cases. In 10 cases thermoradiotherapy was used definitively, and in the other nine cases preoperatively. Radiotherapy was administered with conventional fractionation. Total dose ranged from 42 to 80 Gy (mean 62.9 Gy) for definitive treatment cases, and 38 to 47 Gy (Mean 40.6 Gy) for preoperative cases. Radiofrequency (RF) capacitive hyperthermia was administered twice weekly, immediately after radiotherapy. Total sessions of hyperthermia ranged from 5 to 16 times (mean 9.0) for definitive treatment cases and 3 to 8 times (mean 6.7) for preoperative cases.

Results: The results of thermoradiotherapy group (HTRT group) were compared with our historical control group (RT group); initially unresectable Stage HI NSCLC irradiated definitively with 50 Gy or more (26 cases), or became resectable after radiotherapy and operated (4 cases). As for initial response, there were· 5 complete responses (CRs), 13 partial responses (PRs), and 1 no change (NC) (CR rate 26%, response rate 95%) in the HTRT group, whereas there were no CR, 21 PRs, and 9 NCs in the RT group (CR rate 0%, p < 0.005,  response rate 70%, p < 0.05). Overall 3-year local relapse-free survival and survival rate for the HTRT group was 73% and 37%, respectively, and 20% and 6.7%, respectively, for the RT group (p < 0.01, p < 0.01). The rate of death from uncontrolled primary disease for the HTRT group was significantly lower than for the RT group (21 % vs. 53%, p < 0.03).

Conclusion: Although the number of cases is rather small, thermoradiotherapy in the treatment of locally advanced NSCLC is promising in raising resectability, local control, and, thus, long-term survival.

Background: To overcome the poor prognosis of lung cancer with pleural dissemination, the authors developed postoperative intrathoracic chemo-thermotherapy (PICT). In this report, they present the long-term results for 31 consecutive patients who underwent resection, followed by PICT for lung cancer with pleural dissemination between April 1985 and December 1991.

Methods: Among the patients, there were 26 cases of adenocarcinoma, 3 cases of squamous cell carcinoma, and 1 case each of large and adenosquamous cell carcinoma. Twenty-four of these patients had an initial diagnosis of pleural involvement at thoracotomy. The other seven patients had massive malignant effusion at the time of the initial diagnosis. PICT was started between days 10 to 14 postoperatively. When possible, three courses of this procedure were administered at intervals of 5-7 days.

Results: The 5-year cumulative and 5-year local relapse- free survival rates were 24.6% and 76.3%, respectively. The 3-year and 5-year cumulative survival rates for 14 patients without mediastinal lymph node involvement were 68.4% and 42.7%, respectively. Those rates for 17 patients with mediastinal lymph node involvement were 22.7% and 0%, respectively. The 3-year survival rate in the former group was significantly better than that in the latter group.

Conclusions: These results strongly suggest that in patients with pleural dissemination, PICT may be beneficial for regional disease control and improvement of survival, particularly for patients without mediastinal lymph node involvement. Cancer 1993; 72:426-31.

From April 1985 through March 1988, 24 hang cancer patients with carcinomatous pleuritis were treated with a new combined treatment modality consisting of pulmonary resection and postoperative intrathoracic chemo-thermotherapy (PICf). They consisted of 15 male patients and nine female patients. A majority of the patients (79%) had adenocarcinoma. The PICf was started 10 to 14 days after the operation. Immediately after a bolus intrathoracic injection of cisplatin (eDDP) 50-100 mg, thermotherapy was carried out using 13.56-MHz or 8.00-MHz radiofrequency waves for 60 minutes. The peripleural temperature was precisely monitored in 20 patients. The temperature was successfully maintained above 4rC for 40 minutes in each of two or three treatment courses in 13 patients, with no complications. However, in the other seven patients the therapy resulted in incomplete treatment because of development of a side effect. Cytologic examination of the pleural effusion, which was performed after the completion of PICf, gave a negative result in 16 of 20 patients examined. The median follow-up period was 16 months. Local relapse was recognized in only three cases who received incomplete treatment or in whom no temperature measurement was performed. The overall survival of the treated patients (n = 24) was significantly prolonged in comparison with a historical control group treated by surgery only (n = 17) or exploratory thoracotomy (n = U). Of those 17 patients treated by surgery only, ten patients (59%) died of local relapse. These results suggest that this new treatment modality consisting of pulmonary resection and PICf is useful for the treatment of lung cancer patients with carcinomatous pleuritis, especially in the light of improved local control.

This report discusses a patient with malignant fibrous histiocytoma (MFH) who was successfully treated with thermo-radiotherapy. The patient was treated with 48 Gy of radiotherapy and 4 sessions of hyperthermia. He displayed a tumor on his shoulder which reached a maximum size of 13 cm. The tumor size gradually decreased after the end of the treatments, and 5 months later the tumor had completely disappeared. There has been no recurrence for 18 months.

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We report a case of Pleural Dissemination of invasive Thymoma, which was successfully treated with intrathoracic Chemotherapy following panpleuropneumonectomy intrathoracic Chemothermotherapy in combination with surgery may be a hopeful adjuvant treatment to control pleural disseminated lesions of invasive Thymoma.

This paper describes a case of malignant pleurisy which showed evidence of the effectiveness of a new mode of cancer treatment, intrathoracic chemothermotherapy (lCT). ICT consisted of a bolus intrathoracic injection of 50 mg cis-diamminedichloroplatinum (CDDP) and local heating using 8 MHz radiofrequency waves for 60 min. A patient with multiple lung metastases and malignant pleurisy on both sides due to Ewing's sarcoma was treated on the right side with ICT, along with concomitant systemic administration of 50 mg CDDP. Intrathoracic temperatures were monitored by insertion of thermocouple temperature sensors and temperatures of 43°C or over were successfully maintained for about 40 min during each of three treatments. Although the patient died 3 months later of advanced metastases in the left lung and malignant pleurisy on the left side, lung metastases in the right lung were stable on radiographs, and autopsy results showed no cancerous lesions in the right thoracic cavity, which had been treated with ICT. Since no effective response had been obtained clinically or histologically before starting ICT, despite frequent administration of anti-cancer drugs, we conclude that heat acted synergistically with CDDP on drug-resistant cells in this case.

Patients and Methods: Since 1988, a total of 46 patients have been enrolled in this investigation. All patients had biopsy confirmed histological proof of recurrence and/or were considered to have advanced breast carcinoma. The probability for local control with radiation alone was estimated to be 5 and 25 %. All radiation therapy was delivered using 4, 6, 18, or 21MeV linear accelerator. The choice of beam type and energy was dependant on tumor location, prior radiation dose, and the limiting adjacent normal tissues. Median radiation dose of 50.4 Gy was delivered in 5-6 weeks using 1.8-2.0 Gy daily 5 times weekly. The hyperthermia treatment objective was to deliver 42.0-44.0 degrees C for 45-50 minutes per session twice weekly with a median total of 10 sessions during the above referenced radiation schedule.

Results: A total of 46 patients were eligible for treatment response analysis. A total of 43 patients achieved complete tumor resolution (93.5%) out of 46 cases. There were a total of seven patients who chose to undergo tissue biopsy for a suspected residual nodule, and all seven of these patients were found to have achieved pathological CR. The minimum follow-up was three months and longest follow-up was over 60 months (median of 20 months). There were no significant side effects other than a moderate degree of pain sensations felt by some which required electrode-skin contact adjustments and/or appropriate analgesic medication.

Conclusions: These results show complete responses to a range of radiation doses without serious complications, and suggest that the use of the Thermotron RF-8 capacitive hyperthermia system in combination with conventional radiotherapy is safe and effective on the chest-wall breast cancer recurrences.

Sixteen patients with recurrent esophageal carcinoma who underwent thermo-radiotherapy from 1994 to 2002 were retrospectively analyzed. A total radiation dose was 55.1 ± 9.2 Gy for post-operative recurrence (n = 9) and 46.1 ± 14.3 Gy for post-radiotherapy recurrence (n = 7). Hyperthermia was performed for 42.5 ± 8.0 min immediately after irradiation with radio frequency capacitive heating devices; number of the sessions was 10.7 ± 9.3. Average Tmax in 6 cases was 44~0 ± 4.4°C. The overall local control rate (CR + PR) was 87.5%, and the 5-year cause specific survival rate was 25.0%. Median survival durations were 73.4 months for CR group and 7.0 months for PR + NC group (p <0.001). Thermo-radiotherapy may improve local control in patients with recurrent esophageal carcinoma.

Peritoneal carcinomatosis is a major problem after surgery for serosal-invasive gastric cancer because most patients with peritoneal carcinomatosis die within six months of diagnosis. In this study, we evaluate the efficacy of intraperitoneal chemohyperthermia for gastric cancer patients with peritoneal carcinomatosis. Seventeen gastric cancer patients with peritoneal carcinomatosis, which was confirmed by cytological and/or pathological examination during operation, were treated by removal of the primary tumor. Seven patients consented to receive chemohyperthermia during the postoperative period (hyperthermia group), while 10 patients underwent surgery only (control group). The IO-month disease-free and overall survival rates for the hyperthermia group were 57.1% and 85.7%, respectively, and were higher than those of the control group. No patient in the hyperthermia group had life-threatening complications, such as leakage of intestinal anastomosis, intestinal perforation, bone marrow suppression, or renal dysfunction. In conclusion, postoperative chemohyperthermia appears to improve the prognosis of gastric cancer patients with peritoneal carcinomatosis. This method is feasible, easy to perform, and relatively safe.

Salvage treatment (treatment of recurrent or resistant tumors) is difficult in patients with either residual or recurrent cancer after definitive chemoradiotherapy for esophageal cancer. This report presents the first case of a patient, for whom hyperthermo-chemotherapy was markedly effective for recurrent cervical esophagus cancer after definitive chemoradiotherapy (CRT). The patient was a 66-year-old female, in whom an elevated cervical tumor was detected 10 years after an endoscopic mucosal resection for mid-thoracic esophageal cancer (cTlaNOMO Stage I based on standards of the Japan Esophageal Society). The tumor was diagnosed to be a secondary primary squamous cell carcinoma of the cervical esophagus (cT2N1MO Stage II). Definitive chemo-radiotherapy (a total 75.4 Gy of radiation plus docetaxel) resulted in a complete response. However, a local recurrence was recognized five months later. Although chemotherapy with nedaplatin and 5-FU was performed for 6 months, the recurrent tumor enlarged. Oral S-I (100 mg/ day) chemotherapy was administered on days 1 -28 every 6 weeks. Concurrent with S-l, local hyperthermia delivered with a Thermotron RF-8 (50 minutes) was performed on days I, 8, 15, and 22, every 6 weeks. After the first course of treatment, the tumor disappeared, and this treatment was repeated for 5 cycles on an outpatient basis without any critical side effects. The clinical course of this case suggests that hyperthermo-chemotherapy is a potent salvage treatment for either remnant or recurrent esophageal cancer disease after definitive CRT.

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 Para aortic 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 tumor response was evaluated using computed tomography (CT). The local response rate (complete regression plus partial regression/all tumors) was 88.9%, which seemed to be higher than that of other reports using thermo chemotherapy or radiotherapy alone. The one-year cumulative survival rate was 39.1%.

The basic treatment for gastric carcinoma is surgical resection. Recently however, in order to shrink the tumor, combined modality therapy has been performed for far-advanced gastric cancer and recurrent tumor following surgery. We report two cases of gastric carcinoma treated with remarkably effective hyperthermo-chemo-radiotherapy. The patients had advanced gastric cancer with invasion to the esophagus and stomal recurrent tumor after total gastrectomy. The tumors completely disappeared after the treatment, and the two patients have survived more than a decade since the beginning of treatment. It is considered that hyperthermo-chemo-radiotherapy is useful for some gastric cancers as an option in combined modality therapy.

Gemcitabine (GEM) has improved both overall survival and tumor-related symptoms in patients with advanced pancreatic cancer when compared to 5-FU, and is a widely accepted treatment for such patients. However, pancreatic cancers remain extremely resistant to chemotherapy. Empiric chemotherapy based on GEM has had no major successes in treating patients with advanced disease. The objective of this study was to evaluate the response rate, survival, and toxicity of the sequential combination of GEM and hyperthermia. Between November 2005 and November 2007, 7 patients with unresectable pancreatic cancer received sequential combination therapy with GEM and hyperthermia at the Matsushita Memorial Hospital. Data were then compared with 7 historical controls treated with GEM alone at the same institution. There were no significant differences in age, performance status or UICC stage between the GEM plus hyperthermia and GEM monotherapy groups. The disease control rate (CR + PR + SD) was] 4.3% for patients treated GEM alone and 57.1 % for patients treated with GEM plus hyperthermia. The median survival time was] 98 days for patients treated with GEM alone, and 327 days for patients treated with GEM plus hyperthermia. Combination therapy with GEM and hyperthermia thus improves overall survival when compared with GEM monotherapy (p = 0.0275). The sequential combination of GEM plus hyperthermia showed a potential therapeutic effect, and was at least as effective as GEM monotherapy. To clarify the effects of this combination therapy, a larger prospective clinical trial is required.

The ultimate goal of cancer treatment is to achieve a complete eradication of the cancer. However, patients with terminal cancer are also treated to obtain an improvement in their quality of life (QOL). In this report, we describe the dramatic response of an end-stage pancreatic cancer patient with cachexia to a combination of hyperthermia (HT) and chemotherapy (CH). The patient was treated with a combination of intermittent S-FU /cisplatin (CDDP) therapy and HT. Three months later, the local recurrent cancer had disappeared, the liver metastases were reduced by 80%, the lung metastatic lesion was markedly reduced, tumor markers had returned to normal, and the cachexia had been almost reversed. Performance status (PS) improved from 4 to 1, QOL improved, and the patient survived until his 2S8th hospital day. In this patient, the combination of CH and HT was useful not only for improvement of cachexia, but also for tumor reduction. A possible mechanism leading to this effect is discussed.

Purpose: To evaluate thermometry and the clinical results of radiofrequency (RF) hyperthermia for advanced malignant liver tumors.

Methods and Materials: One hundred seventy-three patients with malignant liver tumors treated between 1983 and 1995 underwent hyperthermia. The 173 tumors consisted of 114 hepatocellular carcinomas (HCCs) and 59 non-HCCs (47 metastatic liver tumors and 12 cholangiocarcinomas). Eight-megahertz RF capacitive heating equipment was used for the hyperthermia. Two opposing 25-cm electrodes were generally used for heating the liver tumors. Our standard protocol was to administer hyperthermia 40-50 min twice a week for a total of eight sessions. The liver tumor temperature was measured by microthermocouples when possible. Transcatheter arterial embolization, radiotherapy, immunotherapy, and chemotherapy were combined with hyperthermia treatment in accordance with each patient's liver function.

Results: One hundred forty (81 %) of the 173 patients who underwent more than four sessions of hyperthermia were evaluated in this study. Thermometry was performed in 77 (55%) of these 140 patients. The maximum tumor temperature, average tumor temperature, and minimum tumor temperature in the HCC were (mean ± standard error) 41.2 ± 0.2°C, 40.3 ± 1.3°C, and 40.1 ± 0.2°C, respectively. The same thermometry results for non-HCC were 42.3 ± 0.2°C, 41.2 ± 0.2°C, and 40.9 ± 0.2°C, respectively. The maximum and minimum temperatures (41.8 ± 0.2°C and 40.3 ± 0.4°C) in the patients with a complete or partial response (CR or PR) were higher than those in the patients with no response or progressive disease (NR or PD) (41.3 ± 0.5°C and 39.8 ± O.4°C), but the difference was not significant. Of the 73 cases with HCC who were evaluated by computed tomography (CT), CR was achieved in 7 (10%), PR in 15 (21 %), NR in 37 (51 %), and PD in 14 (19%). Of the 45 cases involving liver metastases evaluated by CT, CR was achieved in 3 (7%), PR in 17 (38%), NR in 12 (27%), and PD in 13 (29%). The 1-year cumulative survival rate for HCC patients was 30.0%, and the 5-year survival rate was 17.5%. The 1-year survival of non-HCC patients was 32.5%, and the longest survival was 30 months. The sequelae of hyperthermia included focal fat necrosis in 20 patients (12%), gastric ulceration in 4 (2%), and liver necrosis in 1 (1%). The sequelae of thermometry were severe peritoneal pain in seven patients (11%), intraperitoneal hematoma in one (1%), and pneumothorax in one (1%).

Conclusion: Even though the thermometry results for liver tumors were not satisfactory, the treatment results are promising. Further clinical trials of RF capacitive hyperthermia for the treatment of advanced liver tumors should be encouraged.

Background
For many years, the standard treatment of advanced cervical carcinoma has been radiotherapy (RT). However, locoregional failure rates of RT for Stage III or Stage IV cervical carcinoma are high. To clarify the role of thermoradiotherapy (TRT; radiotherapy plus hyperthermia) for FIGO Stage IIIB cervical carcinomas, we investigated both the clinical response and survival of patients treated with radio or thermo radiotherapy. On the other hand, to identify a set of genes related to thermo radiosensitivity of cervical carcinoma, we compared the expression profiles of thermo radiosensitive and thermo radioresistant tumors using a cDNA micro array analysis.

A randomized clinical trials in our study and published trials
in our randomized trials, forty patients with Stage IIIB uterine cervix carcinoma ·were divided randomly into the following two groups: the RT group of 20 patients who underwent R T alone, and the TRT group of 20 patients who underwent three sessions of hyperthermia in addition to R T. A complete response was achieved in 50% in the RT group versus 80% in the TRT group (P=0.048). Both the 5-year overall survival and disease-free survival of the patients who were treated with TRT (58.2% and 63.6%) were better than those of the patients treated with RT (48.1 % and 45%), but these differences were not significant. The 5-year local relapse-free survival of the patients who were treated with TRT (79.7%) was significantly better than that of the patients treated with RT (48.5%) (P=0.048). Six randomized trials comparing the results of RT alone with TRT have been published, of which four showed significant better complete response, locoregional tumor control and/or disease-free survival rates. One trial showed a trend of better locoregional tumor control and one did not show any benefit.

Prediction of advanced cervical carcinoma after thermoradiotherapy using microarray analysis in our previous study
A total of 19 patients with Stage III-IV cervical cancer who underwent definitive thermoradiotherapy were included in this study. We compared the expression profiles of 8 thermoradiosensitive and 11 thermoradioresistant tumors obtained by punch biopsy before treatment using a cDNA micro array. We selected 35 genes on the basis of a clustering analysis, and confirmed the validity of these genes with a cross validation test. Some of these genes were already known to be associated with apoptosis (BIK, TEGT), hypoxia-inducible gene (HIFIA), and tumor cell invasion and metastasis (PLA U). These results may eventually lead to the achievement of "personalized therapy" for this disease.

Purpose: The therapeutic and adverse effects of pre-operative chrono-chemoradiation with local hyperthermia for patients with rectal adenocarcinoma were evaluated.

Materials and methods: Pre-operative radiation therapy of a total dose of 40 Gy (n = 10) or 50 Gy (n = 19) on the whole pelvis and hyperthermia once a week during the radiation therapy for 1 h were performed for patients with T2-T4 rectal adenocarcinoma. Chemotherapy consisted of 5-FU (250 mg m -2 per day) and LV (25 mg m -2 per day) administered by continuous infusion in the night for 5 days a week in the second and fourth weeks of radiation.

Results: Grade 3+ toxicities were seen only in two patients (6.9%). A significant down staging was seen in 41.4% of all cases and 52.6% of cases with a radiation dose of 50 Gy. Of the patients who had received surgical resection of a tumor, three (11.1 %) had no residue pathologically in the specimen and eight (29.6%) had microscopic lesions.

Conclusions: These results yielded a high response rate with minimal toxicities for advanced low-rectal adenocarcinoma. The administration of 5-FU during the sleeping time before irradiation might have an advantage not only as a chronotherapy but also as a radiation sensitizer.

We report a patient with paralysis and severe lumbago due to a vertebral metastasis from rectal cancer that was successfully treated with thermo-radiotherapy plus chemotherapy and hyperbolic oxygen therapy. The patient underwent 40Gy of radiotherapy, 12 sessions of hyperthermia and 16 sessions of hyperbolic oxygen therapy combined with weekly chemotherapy. His symptoms were gradually improved after start of the treatment, lumbago was relieved at the end of radiotherapy, and he became ambulatory. The patient was also treated for other distant metastases with radiotherapy, hyperthermia and chemotherapy continuously with keeping good quality of life during eight months after the completion of the treatments for vertebral metastasis. Combination of radiotherapy, hyperthermia, chemotherapy and hyperbaric oxygen therapy may be effective for complete paralysis due to vertebral metastasis in inoperative cases.

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 (> 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°C, 43.3°C, and 40.6°C, respectively. The corresponding values were 42.ZOC, 41.3°C, and 40.3°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% (I 7/29) 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 H. A better response rate of67% was obtained in the U5 tumors with a mean average tumor temperature of 42°C. Although limitation of our current heating devices exists, the combination of hyperthermia with radiotherapy is a promising treatment modality in the treatment of locally advanced colorectal cancer.

Recently, organ-preserving regimens using predominantly multiple-modality therapy, consisting of endoscopic transurethral resection followed by irradiation with concurrent chemotherapy, are emerging as viable alternatives for muscle-invasive bladder cancer, although radical cystectomy has been the standard treatment. Three cases with muscle-invasive bladder cancer (5-7 cm in size), two of T2N 1 MO and one of T2NOMO, underwent bladder preservation therapy with regional hyperthermia for improvement of the local effect. A total dose of 66-70Gy in the conventional methods, chemotherapy composed of methotrexate, doxorubicin, cisplatin and/or vinblastine, and 3 to 12 sessions of hyperthermia during radiotherapy were delivered. All three cases showed complete response without any local recurrence or distant metastasis in follow-ups. Toxicity during the treatment was acceptable, and late toxicity was not recognized. Bladder preservation therapy adding regional hyperthermia is potentially useful for improving the treatment results for muscle-invasive bladder cancer of large tumor size.

This case report describes a 40 year old man with a fibrosarcoma arising from the left lower extremity. The tumor was seated deeply in the left lower extremity and the tumor size was 13 cm in diameter and 24 cm in length. The patient was treated with a preoperative combination of hyperthermia and radiotherapy followed by a limb-sparing surgical resection. Radiation therapy was delivered using a Linac 6-MV X-ray with two opposed beams. The dose was 3 gray (Gy) per fraction, 5 times per week, for a total dose of 30 Gy. Hyperthermia was given twice a week, and started within 15 minutes after irradiation. Hyperthermia was performed using a Thermotron RF-8, and applied for approximately 40 minutes to achieve a temperature of over 42°C in the tumor. Limb-sparing surgical resection was performed eight days after the completion of radiotherapy and hyperthermia. No local recurrence was observed after 67 months. Furthermore, no serious complications were observed after surgery, and the function of the limb has been completely preserved. A combination of preoperative thermoradiotherapy and marginal resection for fibrosarcomas arising in the lower extremities may offer a useful therapy for preserving function and for local control. This report describes a fibrosarcoma case arising from a lower extremity which was successfully treated by thermoradiotherapy and limb-sparing surgical resection.

Purpose: Since 1985, the University of Minnesota Hospital and Clinic has investigated the efficacy and safety of 8 MHz radiofrequency (RF) capacitive hyperthermia using the Thermotron RF -8. This study reports the thermometric and clinical results of 119 patients treated with RF hyperthermia in combination with radiotherapy (RT).

Methods and Materials: Of 119 patients, 69 received high-dose RT and 50 patients received low-dose RT because of previous irradiation to the treatment site. The most common anatomic sites treated were within the pelvic cavity or head and neck area. Thirty-three percent and 24% of tumors treated were> 7 cm and > 10 cm in largest diameter, respectively. Forty percent of the patients had deep-seated tumors (depth > 6 cm). Hyperthermia was given as soon as possible after RT twice weekly, allowing at least 72 h between treatments. The objective was to raise intra-tumoral temperatures to 42-43°C or above for 30-50 min while keeping normal tissue temperatures below 40-4JDC.

Results: Of 119 patients, 40% achieved a TiDaX tumor temperature of > 42°C and 40% achieved 40-42°C T max, Higher T max tumor temperatures were observed as tumor size increased. Tumors > 10 cm in largest diameter had a TiDaX of 42.2°C. Tumor depth was not a significant factor for the tumor temperatures achieved. Of 119 patients, 11 % achieved complete response and 38% achieved partial response. Of the no response patients, 34% had symptomatic palliation and 15% had stable disease for at least 12 months after treatment. We were able to treat tumors of patients with subcutaneous fat as thick as 3 cm by precooling the fat for 20 min with 10-15°C saline-filled boluses prior to the initiation of heating. During treatment, 60 % of patients complained of varying degrees of pain and 19 % had pain that was a factor in limiting treatment. Vital signs were relatively stable and not a factor in limiting treatment.

Conclusion: The Thermotron RF -8 is a useful hyperthermia device that can raise tumor temperatures to a therapeutic level (i.e., 42°C) in a significant proportion of patients with superficial, subsurface, and deep-seated tumors, with minimal adverse effects, complications, and systemic stress. Further clinical studies using improved thermometry systems are warranted.

Although mild hyperthermia (MHT) cannot directly kill tumor cells, an augmented immunological effect resulting from MHT has been reported to induce injury of malignant tumors. In this study, the impact of regional MHT on lymphocyte subpopulations was investigated. Of particular interest was the effect of MHT on natural killer (NK) cells and T cells, which are important in the innate and adaptive immune systems. Regional MHT treatment was performed using an 8-MHz capacitive heating device, the Thermotron RF8 (Yamamoto Vinita Co., Ltd., Osaka, Japan). An average continuous radio-frequency irradiation of approximately 900 W was applied between two 30-cm electrodes placed on opposite sides of a volunteer's upper abdominal region for 30 min. In healthy volunteers exposed to this thermal treatment, NK cell activity and the percentage of NK cells and cytolytic NK cells (CD3-CD56dim cells) in lymphocyte populations increased significantly at I and7 days after regional MHT treatment compared with pre-treatment numbers. The number of cytolytic NK cells also increased significantly at I day after treatment. The percentage of T cells and CD4+ T cells decreased significantly from I to 7 days following the heating procedure. However, no significant changes in the percentage and the number of CD8+ T cells were observed. Interestingly, the percentage and the number of CD4+CD25+ T lymphocytes which are recognized as regulatory T lymphocytes (Treg) decreased significantly during the 7 day post-treatment period. These results suggest that regional MHT may activate both, the innate and adaptive immune systems, through activation of NK cells and through a decrease in the number of regulatory T cells.

Improvement in the quality of life (QOL) is considered to be one of the main goals in the treatment of patients with advanced cancer. The purpose of this study was to assess the QOL for patients during the course of combined treatments which included local hyperthermia (HT) plus chemotherapy and/ or radiotherapy. Eighty nine patients (M/F ratio was 44/45) with various malignancies were questioned using the Japanese version of the 'European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire Core 30'. Assessment was performed before the beginning of HT therapy, and after 8 weekly sessions. In addition, a longitudinal study was performed with 14 patients after 16, 24 and 30 sessions. It was seen that gender may influence various aspects of the QOL during the treatments. For instance, female patients performed better with regards to the social aspects whereas they displayed worse somatic parameters. Regarding age, although younger patients claimed more financial problems before HT, onset of HT did not cause any additional difficulties in this respect. Surprisingly, HT led to a better recovery from a loss of appetite in elderly patients. In considering the relationship between the QOL and treatment response, better responses were associated with both superior pretreatment emotional functioning and improvement in the QOL during the therapy. The best QOL performance was observed for patients with breast and lung cancer. In addition, patients who underwent long-term HT which lasted for 36 weeks had stable QOL parameters throughout the entire period of observation. This leads us to suggest that somatic, social and psychological QOL parameters for cancer 'patients may be improved by combined treatment modalities which include HT. In addition, both pretreatment emotional status and improvement in the QOL during the course of treatment may influence the objective treatment outcome.