title: Regional hyperthermia combined with radiotherapy for uterine cervical cancers: a multi-institutional prospective randomized trial of the international atomic energy agency.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Radiation Oncology, Cancer Institute, Chennai, India.
authors.forename: Arumugam
authors.initials: A
authors.lastname: Vasanthan
authors.forename: Michihide
authors.initials: M
authors.lastname: Mitsumori
authors.forename: Jeong Ho
authors.initials: JH
authors.lastname: Park
authors.forename: Zeng
authors.initials: Z
authors.lastname: Zhi-Fan
authors.forename: Zhong
authors.initials: Z
authors.lastname: Yu-Bin
authors.forename: Praskovya
authors.initials: P
authors.lastname: Oliynychenko
authors.forename: Hideo
authors.initials: H
authors.lastname: Tatsuzaki
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiraoka
mesh_terms: D000328:Adult; D000368:Aged; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced / Q000009:adverse effects / Q000379:methods*; D008875:Middle Aged; D011446:Prospective Studies; D011878:Radiotherapy / Q000379:methods; D011879:Radiotherapy Dosage; D015996:Survival Rate; D002583:Uterine Cervical Neoplasms / Q000401:mortality / Q000532:radiotherapy / Q000628:therapy*