Critical Analysis of Electromagnetic Hyperthermia Randomized Trials: Dubious Effect and Multiple Biases

Table 6

Randomized clinical trials on deep local hyperthermia published after 1990.

Clinical trial	Emami et al. [20]	van der Zee et al. [21]			Mitsumori et al. [22]	Vasanthan et al. [15]	Issels et al. [23]	Harima et al. [24]
Sponsor	RTOG	Dutch Deep Hyperthermia Group			IAAE	IAAE	ESHO, EORTC, NIH	N/A
Year of publication	1996	2000			2007	2005	2010	2001
Enrollment period	1986–1992; 6.5 years	1990–1996; 6 years			1988–2002; 3.5 years	1998–2002; 3.5 years	1997–2006; 9.5 years	1994–1999
		358						40
Number of patients	184 (173)				80	110	341
		114	143	101
Age
HT+		51	62	73		50	51	65
HT−		50	64	69		45	52	62
Tumor type	Deep-seated tumors of head and neck and pelvis	Loc. adv. cervical cancer	Loc. adv. rectal cancer	Loc. adv. bladder cancer	Locally advanced NSCLC	Locally advanced carcinoma of the uterine cervix	Soft tissue sarcoma	Loc. adv. cervical cancer
Pretreatment	Heavy: 84% RT, 45% surg, 34% ChT	No			No	No	No	No
Comparison	TRT versus RT alone	TRT versus RT alone			TRT versus RT alone	TRT versus RT alone	TChT versus ChT in complex treatment	TRT versus RT alone
Base treatment	EBRT; TD ≤ 100 Gy	EBRT + BT; TD = 65 Gy	EBRT; TD 66–70 Gy	EBRT; TD 66–70 Gy	EBRT	EBRT + BT; TD = 84 Gy	ChT (EIA) → surgery → RT → ChT (EIA)	EBRT + BT; TD = 82.2 Gy
HT unit(s)	N/A	3 units: BSD2000, TEM, 4-guide			Thermotron-RF8	Thermotron-RF8	BSD2000	Thermotron-RF8
HT protocol	42.5°C × 30–60′, 1 (before RT) or 2 (bef/aft RT) HTs	42°C × 60′, 5 HTs after RT 1/week			42°C × 60′, 5 HTs after RT 1/week	42°C × 60′, 5 HTs after RT 1/week	42°C × 60′, 16 HTs interval 3 days	42°C × 60′, 3 HTs after RT 1/week
Complete local response (CLR)
HT+	CLR 55%	CLR 55% (𝑃<0.001)					CLR + PLR = 34% (𝑃=0.02)	80%
		CLR 83%	St.insign.		Statistically insignificant (𝑃=0.49)
HT−	CLR 53%	CLR 39% (𝑃<0.001)					CLR + PLR = 16% (𝑃=0.02)	50%
		CLR 57%	St.insign.
Overall survival (OS)
HT+	34% (2 y)	51% (3 y)			Statistically insignificant  (𝑃=0.868)	73.2% (3 y); (𝑃=0.19)	79 mnth (𝑃=0.43)	58% (3 y)
HT−	33% (2 y)	27% (3 y)					74 mnth (𝑃=0.43)	48% (3 y)
Local Progression free survival (LPFS)
HT+					Significantly better  (𝑃=0.036)	68.5% (3 yrs); (𝑃=0.58)	66% (4 y) (𝑃=0.003)
HT−							55% (4 y) (𝑃=0.003)
Progression-free survival (PFS)
HT+							32 mn (𝑃=0.011)
HT−							18 mn (𝑃=0.011)
Common toxicity
HT+	3-4 Grade—22%					17% Gr2, 1% Gr3	96.4% (𝑃=0.005)
HT−	3-4 Grade—12%					4% Grade 2	78.5% (𝑃=0.005)