TABLE 3.

List of randomized clinical trials on hyperthermia combined with radiotherapy or/and chemotherapy.

Reference	Cancer type	Method	Number of patients randomized	Type of treatment	Outcomes	Toxicity from hyperthermia
Johannsen et al. (2005a)	Malignancy ≤3 cm in thickness from the body surface	MIH + radiotherapy	109	All patients received hyperthermia (radiative hyperthermia, 433 MHz, for ≤1 h maximum allowable temperature of normal tissue 43°C) for 1 h. If they were unable to achieve a thermal dose of ≥0.5 CEM 43°C T90, they were not randomized. Rest of patients were then randomized. Control: No further hyperthermia but had radiotherapy Experimental: Hyperthermia + radiotherapy (twice a week, 1–2 h, targeted between 10 and 100 cumulative equivalent minutes at 43°C T90)	Complete response rate: Hyperthermia arm 66% Control arm 42% p = 0.02 Note that some patients received systemic treatment but there was no significant difference in the proportion of patients in each arm who received systemic therapy No significant difference in overall survival	Grade 1 and 2 thermal burns 41% in experimental arm 4% in control arm Grade 3 thermal burns 5% for experimental arm 2% in control arm 11% catheter (used to monitor the temperature) related side effects for experimental arm 2% for control arm
Franckena et al. (2008)	Locoregionally advanced cervical cancer	MIH + radiotherapy	114	Control arm: Radiotherapy Experimental arm: Radiotherapy + hyperthermia (via various systems depending on site, >42°C for 60 min, 5 treatments)	12 years follow-up Local control: 37% for hyperthermia arm 56% for control p = 0.01	Similar rates of late toxicity between control and experimental arm
Huilgol et al. (2010)	T2-T4, N0-N3, M0 Oropharynx, hypopharynx or oral cavity carcinoma	MIH + radiotherapy	56	Control Arm: Radiotherapy Experimental Arm: Radiotherapy + hyperthermia (via capacitive system, 8.2 MHz, power increased until patients complained of discomfort, power reduced and treatment continued for 30 min, 5–7 sessions)	Statistically significant difference in median survival of control group 145 days Experimental group 241 days	Comparable acute and late toxicities between control and experimental arm, except for overall increase in thermal burns in the experimental arm
Kitamura et al. (1995)	Squamous cell carcinoma of the thoracic esophagus undergoing neoadjuvant therapy	MIH + chemotherapy	66	Control arm: Neoadjuvant chemoradiotherapy + surgery Experimental arm: Neoadjuvant hyperthermia or radiotherapy (capacitive system involving an intraluminal applicator, 42.5°C–44°C at tumor surface for 30 min, 6 sessions)	Complete response 25% in experimental arm 5.9% in control arm 3 years survival 50.4% experimental arm 24.2% control arm	Details lacking No postoperative mortality in either arm
Sneed et al. (1998)	Glioblastoma	MIH + chemotherapy	79	Control arm: Radiotherapy + oral hydroxyurea + brachytherapy boost Experimental arm: Radiotherapy + oral hydroxyurea + brachytherapy boost + hyperthermia (radiative hyperthermia, 915 MHz, ≥42.5°C for 30 min, 15–30 min before and after brachytherapy)	Median survival 76 weeks for control arm 85 weeks for hyperthermia arm p = 0.02	There was a trend (p = 0.08) toward more grade 3 or higher toxicities for the experimental arm Higher incidence of grade 1 and grade 2 neurological changes and seizures for the experimental arm
Issels et al. (2010)	Localised high-risk soft-tissue sarcoma, extremity and retroperitoneal	MIH + chemotherapy	341	Control arm: Neoadjuvant and adjuvant chemotherapy (etoposide, ifosfamide, doxorubicine) + local therapy (surgery +/radiotherapy) Experimental arm: Neoadjuvant and adjuvant chemotherapy (etoposide, ifosfamide, doxorubicine) + local therapy (surgery ± radiotherapy) + regional hyperthermia (radiative hyperthermia, 42°C for 60 min on day 1 and 4 of 3 weekly chemotherapy cycles, up to 8 sessions)	Median follow-up 34 months Significant improvement in local progression-free survival (hazard ratio = 0.58, p = 0.003) and disease-free survival (hazard ratio = 0.7, p = 0.011)	Increased pain, bolus pressure, skin burn in experimental arm