Regional hyperthermia combined with radiotherapy for uterine cervical cancers: a multi-institutional prospective randomized trial of the international atomic energy agency. Multi-institutional clinical studies on hyperthermia combined with radiotherapy or chemotherapy in advanced cancer of deep-seated organs. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Dutch Deep Hyperthermia Group. Local thermo-radiotherapy in carcinoma cervix: improved local control versus increased incidence of distant metastasis. Thermoradiotherapy of patients with locally advanced carcinoma of the rectum.
Hyperthermia can be used to enhance the effects of radiation, and a combined treatment may, in some circumstances, be an advantage. Uterine cervical cancer is very common in developing countries. The control of locally advanced pelvic tumors is difficult with conventional treatment modalities. Based upon the biologic rationale and in view of the recent advances in heating and thermometry techniques, radiotherapy in combination with hyperthermia was investigated in a multi-institutional prospective randomized trial sponsored by the International Atomic Energy Agency. The primary purpose was to clarify whether the combination of hyperthermia and radiotherapy improves the rate of local control, compared with radiotherapy alone.
                A total of 110 patients with biopsy-proven, locally advanced carcinoma of the uterine cervix were randomized to treatment by radiotherapy with or without hyperthermia. The patients were stratified by institution, stage, and histologic type. Each patient received external beam radiation therapy and brachytherapy. For the patients randomized to receive hyperthermia, a minimum of five sessions (60 min each, once per week) were administered, employing a radiofrequency (RF) capacitive heating device. Intratumoral temperature was measured at the first hyperthermic treatment, and at least once more during the course of treatment. The equipment and the policies and procedures at each participating institution except one (Pusan) were personally inspected at least once by the corresponding author, to ensure that quality assurance procedures were in place and were followed for treatment according to the protocol guidelines. The median follow-up period was 466 days for all the patients and 512 days for the surviving patients.
                The two arms were well balanced with regard to the patient factors, tumor factors, and treatment factors. The overall survival rate at 3 years was 73.2%, and the local control rate was 68.5%. There were no significant differences between the patients treated with or without hyperthermia, either with regard to the survival (p = 0.1893) or the rate of local control (p = 0.58). The survival was significantly worse among the patients with Stage IIb disease who received hyperthermia (p = 0.0162) although there was no difference in their rate of local control (p = 0.7988). Further analysis is necessary to determine if the difference in survival is due to a greater incidence of distant metastases or some other cause. Acute Grade 2-3 toxicity was seen in 10/55 patients (18%) treated by hyperthermia and in 2/55 of the patients (4%) treated without hyperthermia (p = 0.01). There was no significant difference in the late toxicity observed in the two arms.
                This prospective randomized study failed to show any benefit from the addition of hyperthermia to radiotherapy in the treatment of locally advanced carcinoma of the uterine cervix. The acute toxicity was significantly greater among the patients receiving hyperthermia, and the survival was significantly worse among the Stage IIb patients receiving hyperthermia even though there was no difference in the local control rate. Multi-institutional studies on clinical hyperthermia of deep-seated tumours were undertaken using 8 MHz radiofrequency capacitive heating devices (Thermotron RF-8) at seven institutions. Each institute was designated to treat specific organs. This paper contains the accumulations of the results obtained at different institutions charged for different tumours. Deep-seated tumours in the lung, stomach, pancreas, liver, urinary bladder and rectum were treated. A total of 177 cases examined from January 1985 to December 1988 included 96 cases (54%) treated with radiotherapy plus hyperthermia, among which 14 cases were pre-operative. Of 177 cases, 81 (46%) were treated with chemotherapy plus hyperthermia. Complete response (CR) and partial response (PR) were obtained in 80% of the cases with lung cancer, 39% with stomach cancer, 56% with liver cancer, 35% with pancreas cancer, 71% with urinary bladder cancer, 100% with primary rectal cancer, and 47% with recurrent rectal cancer. Thermometry was performed using two techniques; one is direct measurement of intratumour temperature in lung and liver cancers, the other is indirect measurement of intracavitary temperature for stomach, pancreas, urinary bladder and rectal cancers. Intratumour temperatures were measured in 30 of the 43 tumours of the lung and liver. The maximum tumour temperature was greater than 42 degrees C in 23 (77%) of the 30 tumours. Intracavitary temperatures were measured in 133 (99%) of the 134 tumours of stomach, pancreas, urinary bladder and rectum. An intracavitary temperature greater than 42 degrees C was obtained in 98 (73.7%) of the 133 tumours. The contribution of hyperthermia in improving the quality of life of patients under terminal care was also investigated. It was indicated that hyperthermia was one of the most effective treatment techniques for advanced or inoperable cases. In this study local control rate (LCR) was mainly discussed because the period of follow-up was only 3 years. Side-effects were observed in 37 cases (21%); main side-effects were fatty induration, pain during treatment and burn. However, no side-effects were severe enough to interrupt therapy. Local-control rates after radiotherapy for locally advanced tumours of the bladder, cervix, and rectum are disappointing. We investigated the effect of adding hyperthermia to standard radiotherapy.
                The study was a prospective, randomised, multicentre trial. 358 patients were enrolled from 1990 to 1996, in cancer centres in the Netherlands, who had bladder cancer stages T2, T3, or T4, NO, MO, cervical cancer stages IIB, IIIB, or IV, or rectal cancer stage M0-1 were assessed. Patients were randomly assigned radiotherapy (median total dose 65 Gy) alone (n=176) or radiotherapy plus hyperthermia (n=182). Our primary endpoints were complete response and duration of local control. We did the analysis by intention to treat.
                Complete-response rates were 39% after radiotherapy and 55% after radiotherapy plus hyperthermia (p<0.001). The duration of local control was significantly longer with radiotherapy plus hyperthermia than with radiotherapy alone (p=0.04). Treatment effect did not differ significantly by tumour site, but the addition of hyperthermia seemed to be most important for cervical cancer, for which the complete-response rate with radiotherapy plus hyperthermia was 83% compared with 57% after radiotherapy alone (p=0.003). 3-year overall survival was 27% in the radiotherapy group and 51% in the radiotherapy plus hyperthermia group. For bladder cancer, an initial difference in local control disappeared during follow-up.
                Hyperthermia in addition to standard radiotherapy may be especially useful in locally advanced cervical tumours. Studies of larger numbers of patients are needed for other pelvic tumour sites before practical recommendations can be made. In 1986, 50 patients with stages II and III carcinoma of the cervix were entered into this prospective randomized study. Twenty-five cases (Group I) were treated only by radical radiation whereas remaining 25 cases (Group II) received local hyperthermia in addition to radical radiation. Hyperthermia was delivered by intracavitary brachyhyperthermia approach using an endotract applicator. Both the groups were followed up for a minimum period of 18 months. Group II patients achieved better local control (14 out of 20 evaluable cases) than the Group I patients (11 out of 22 evaluable cases). A disturbing observation was the increased incidence of distant metastasis in Group II (4 out of 23 cases) as compared to Group I (1 out of 23 cases), though most of them remained disease free locally. The increasing use of hyperthermia in the management of various cancers needs to be reviewed in this context. The effectiveness of local hyperthermia was investigated in 56 patients with locally advanced carcinoma of the rectum (T4N0M0). All received combined heat and radiation therapy as a pre-operative treatment. The control group consisted of 59 patients with the same stage of disease as those who were only irradiated. Both groups of patients underwent the same surgical procedure. The total tumour dose of ionizing radiation was 40 Gy in 10 fractions, three times a week. The tumour was heated four or five times to a maximum of 42-43 degrees C by electromagnetic waves with a frequency of 905 MHz before irradiation. Each heating session lasted 60 min. Patients were selected on the principle of randomization: 16.1% of patients (n = 9; n: actual number of patients) showed complete response and 53.6% (n = 30) showed significant regression of the primary tumour compared with 1.7% (n = 1) and 33.9% (n = 20) in the control group, respectively. The differences were significant (p less than 0.05). It was found that thermoradiotherapy allowed the 5-year survival rate of patients to increase up to 35.6% (n = 12) compared with 6.6% (n = 7) in the control group (p less than 0.05).
Further studies are needed to compare chemoradiation versus thermoradiation versus chemoradiation plus hyperthermia in well selected/conducted and quality controlled randomised trials.