Hyperthermia, cisplatin and radiation trimodality treatment: A promising cancer treatment? A review from preclinical studies to clinical application

Figures & data

Table I.  Phase II clinical studies for trimodality treatment consisting of hyperthermia, cisplatin and radiotherapy.

Tumor location	Total patients	Hyperthermia	Cisplatin	Radiation	Sequence	%CR	Reference
Superficialmalignancies	24	6 × (once per wk) for 60 min	6 × 20, 30 or 40 mg/m^2	18–24 × 2 Gy for fulldose tolerance	HT + cDDP → X	50	[35]
Breast	36	? × (once per wk) for 60 min	? × 40 mg/m^2	? × 4 Gy	HT + cDDP → X	53 for all treatments	[36]
Head and neck	18	2 × (once per wk) for 30–60 min	7 × 20 mg/m^2	35 × 2 Gy	cDDP → X → HT	72	[37]
Head and neck	36	>2 × (twice per wk) for 45 min	3–5 × 20 mg/m^2	15–39.9 Gy (implant)or 25.2–64 Gy(external beam)	cDDP → HT → X	93	[38]
Head and neckand sarcoma	26	4 × (once per wk) for 60 min	4 × 40 mg/m^2	15–35 × 2 Gy	X → HT + cDDP	19	[39]
Head and neck	21	3–8 × (twice per wk) for 60 min	2–6 × 30 mg/m^2	30–35 × 2 Gy	cDDP → X → HT	40	[40]
Head and neck	53	6 × (twice per wk) for 60 min	6 × 30 mg/m^2	35 × 2 Gy	cDDP → X → HT	82	[41]
Oesophagus	294	6 × (twice per wk) for 30 min	3 × 40 mg/m^2	15 × 2 Gy	X → HT + cDDP	35	[42]
Oesophagus	317	6 × (twice per wk) for 30 min	3 × 40 mg/m^2	15 × 2 Gy	X → HT + cDDP	30	[43]
Oesophagus	322	6 × (timing and duration unknown)	3 × 40 mg/m^2	Unknown	Unknown	35	[44]
Cervix	12	5 × (once per wk) for 60 min	5 × 40 mg/m^2	25–28 × 1.8 Gy	X → HT + cDDP	92	[45]
Cervix	68	5 × (once per wk) for 60min	5 × 40 mg/m^2	5 × 1.8–2.0 Gy+brachytherapyboost	HT + cDDP → X orX → HT + cDDP	90	[46]
Cervix	32	5 × (once per wk) for 60 min	5 × 40 mg/m^2	25 × 1.8 Gy	X → HT + cDDP	–	[47]

Note: ?= Unknown.

Table II.  Trimodality treatment consisting of hyperthermia, cisplatin and radiotherapy in animals.

System	Hyperthermia	Cisplatin	Radiation	Sequence	Treatment outcome*			Reference
FSaIIC fibrocarcinoma in	Local	10 mg/kg	5 × 3 Gy	cDDP	TGD 8.0 days			[50], [51]
C3H/He mice	43°C, 30 min			HT	TGD 1.4 days
				cDDP → HT	TGD 5.9 days
				X	TGD 6.3 days
				HT → X	TGD 8.4 days
				cDDP → X	TGD 11.7 days
				X → cDDP + HT	TGD 13.9 days
				cDDP → X → HT	TGD 19.3 days
				cDDP + HT → X	TGD 25.2 days
Spontaneous mammary carcinoma from C3H/Tif injected in C3H/Tif/Bom x D2BA/Bom F1 mice	Local43.5°C, 60 min	6 mg/kg	10–65 Gy	X X → 4 h → cDDP	TCD50 54.4 Gy	TCD50 Air	TCD50 Clamped	[52]
			X → 4 h → HT	54.6 Gy	54.4 Gy	64.2 Gy
			X → 15 min → cDDP → 3.75 h → HT	30.3 Gy	54.6 Gy	57.0 Gy
				31.9 Gy	30.3 Gy	47.1 Gy
				32.5 Gy	31.9 Gy	40.4 Gy
FSaIIC fibrocarcinoma in C3H/He mice	Local	10 mg/kg	10 Gy	HT		Bright	Dim	[53]
43°C, 30 min			X		∼ 50%	∼ 15%
				cDDP		∼ 10%	∼ 20%
				HT → X		∼ 15%	∼ 40%
				cDDP → HT		∼ 5%	∼ 2%
				cDDP → X		∼ 0.5%	∼ 1%
				cDDP → HT → X		∼ 1.5%	∼ 7%
						∼ 0.01%	∼ 0.08%
Sarcoma-180 in BALB/c mice	Local	2.5 mg/kg	10 Gy	Untreated	0% CR			[54]
43°C, 30 min and42°C, 60 min				cDDP	19% CR
				X	38% CR
				HT (43°C, 30 min)	25% CR
				HT (42°C, 60 min)	45% CR
				cDDP → X	65% CR
				X → HT (43°C, 30 min)	59% CR
				cDDP → HT(42°C, 60 min)	65% CR
				cDDP → HT (43°C, 30 min)	70% CR
				cDDP → X → HT (42°C, 60 min)	Too toxic
				cDDP → X → HT (43°C, 30 min)	100% CR
SCCHN in nude mice	Local	2 mg/kg	5 × 2 Gy	X	CR 2/15			[55]
	41.0 and 41.8°C,60 min			X → HT (41°C)	CR 5/15
				X → HT (41.8°C)	CR 7/15
				X → cDDP + HT (41°C)	CR 6/15
				X → cDDP + HT (41.8°C)	CR 12/15

*Treatment outcome is determined by using different endpoints: TGD [50], [51]: the days taken by each individual tumour to reach 500 mm³ compared with the untreated controls. TCD₅₀ [52]: the radiation dose, which on average results in tumour control in half of the treated animals, with: TCD₅₀ air: TCD₅₀ in aerobic cells, TCD₅₀ clamped: TCD₅₀ in hypoxic cells. Bright: survival of oxygenated cells, Dim: survival of hypoxic cells [53]. CR, complete response [54]: complete regression with no regrowth during the 120 days of observation. CR, complete remission [55]: the absence of tumour up to day 60. Trimodality treatments and corresponding treatment outcomes are shown in bold.

Table III.  Trimodality treatment consisting of hyperthermia, cisplatin and radiotherapy in cell lines.

				Cell line
Hyperthermia	Cisplatin	Radiation	Sequence	cDDP sensitive	Synergy?	Enhancement*	cDDP resistant	Synergy?	Enhancement*	Reference
40°C, long duration	1 µg/ml, long duration	LDR	Concomittant	Glioma	Yes	–	Glioma	Small	1.35 (DMF)	[84]
40°C, 1 h	1 and 3 µg/ml, 1 h	LDR	HT + cDDP → X	Ovariancarcinoma	Yes (3 µg/ml)	2.7 (RR)	Ovariancarcinoma	No	–	[79]
			X → HT + cDDP		Yes (3 µg/ml)	2.8 (RR)		No	–
40°C, 1 h	1 and 3 µg/ml, 1 h	HDR	CDDP → X → HT	Ovariancarcinoma	Yes	3.6 (RR)	Ovariancarcinoma	Yes	3 (RR)	[80]
			X → HT + cDDP		Yes (3 μg/ml)	4.6 (RR)		Yes	1.2 (RR)
40°C, long duration	0.5–3 µg/ml, long duration	LDR	Concomittant	Ovariancarcinoma	Yes	–	Ovariancarcinoma	Yes	–	[83]
41°C, 1 h	1–10 µM, 1 h	HDR	HT + cDDP → X	Cervicalcarcinoma	No	–	NSCLC	No	–	[81]
43°C, 1 h	1–10 µM, 1 h		HT + cDDP → X		No	–		No	–
41°C, 1 h	1 µM, continuously		HT + cDDP → X		Yes	2.0 (RER)		No	1.1 (RER)
43°C, 1 h	5 µM, continuously		HT + cDDP → X		Too cytotoxic	–		Yes	2.1 (RER)

*Enhancement is determined by using different ratios:

 DMF (Dose Modifying Factor at 10% survival): The dose required by one treatment to obtain 10% survival divided by the dose required to obtain the same survival level for combined treatments.  RR (Recovery Ratio): the survival after a specific incubation time divided by the survival for zero incubation time.  RER (Radiation Enhancement Ratio at 10% survival): The radiation dose necessary to decrease survival to 10% after radiation alone divided by the radiation dose necessary to decrease survival to  10% after combined treatment.

Herman TS, Jochelson MS, Teicher BA, Scott PJ, Hansen J, Clark JR, Pfeffer MR, Gelwan LE, Molnar-Griffin BJ, Fraser SM. A phase I–II trial of cisplatin, hyperthermia and radiation in patients with locally advanced malignancies. Int J Radiat Oncol Biol Phys 1989; 17: 1273–1279

 PubMed Web of Science ®Google Scholar

Bornstein BA, Zouranjian PS, Hansen JL, Fraser SM, Gelwan LA, Teicher BA, Svensson GK. Local hyperthermia, radiation therapy, and chemotherapy in patients with local-regional recurrence of breast carcinoma. Int J Radiat Oncol Biol Phys 1993; 25: 79–85

 PubMed Web of Science ®Google Scholar

Amichetti M, Graiff C, Fellin G, Pani G, Bolner A, Maluta S, Valdagni R. Cisplatin, hyperthermia, and radiation (trimodal therapy) in patients with locally advanced head and neck tumors: A phase I–II study. Int J Radiat Oncol Biol Phys 1993; 26: 801–807

 PubMedGoogle Scholar

Schreiber DP, Overett TK. Interstitial hyperthermia and iridium-192 treatment alone vs. interstitial iridium-192 treatment/hyperthermia and low dose cisplatinum infusion in the treatment of locally advanced head and neck malignancies. Int J Radiat Oncol Biol Phys 1995; 33: 429–436

 PubMedGoogle Scholar

Feyerabend T, Steeves R, Wiedemann GJ, Weiss C, Wagner T, Richter E, Robins HI. Local hyperthermia, radiation, and chemotherapy in locally advanced malignancies. Oncology 1996; 53: 214–220

 PubMedGoogle Scholar

Serin M, Erkal HS, Cakmak A. Radiation therapy, cisplatin and hyperthermia in combination in management of patients with recurrent carcinomas of the head and neck with metastatic cervical lymph nodes. Int J Hyperthermia 1999; 15: 371–381

 PubMed Web of Science ®Google Scholar

Serin M, Erkal HS, Cakmak A. Radiation therapy, cisplatin and hyperthermia in combination in management of patients with carcinomas of the head and neck with N2 or N3 metastatic cervical lymph nodes. Radiother Oncol 1999; 50: 103–106

 PubMed Web of Science ®Google Scholar

Saeki H, Kawaguchi H, Kitamura K, Ohno S, Sugimachi K. Recent advances in preoperative hyperthermochemoradiotherapy for patients with esophageal cancer. J Surg Oncol 1998; 69: 224–229

 PubMed Web of Science ®Google Scholar

Morita M, Kuwano H, Araki K, Egashira A, Kawaguchi H, Saeki H, Kitamura K, Ohno S, Sugimachi K. Prognostic significance of lymphocyte infiltration following preoperative chemoradiotherapy and hyperthermia for esophageal cancer. Int J Radiat Oncol Biol Phys 2001; 49: 1259–1266

 PubMed Web of Science ®Google Scholar

Ohga T, Kimura Y, Futatsugi M, Miyazaki M, Saeki H, Nozoe T. Surgical and oncological advances in the treatment of esophageal cancer. Surgery 2002; 131: S28–S34

 Google Scholar

Jones EL, Samulski TV, Dewhirst MW, Alvarez-Secord A, Berchuck A, Clarke-Pearson D, Havrilesky LJ, Soper J, Prosnitz LR. A pilot Phase II trial of concurrent radiotherapy, chemotherapy, and hyperthermia for locally advanced cervical carcinoma. Cancer 2003; 98: 277–282

 PubMed Web of Science ®Google Scholar

Westermann AM, Jones EL, Schem BC, van der Steen-Banasik EM, Koper P, Mella O, Uitterhoeve AL, de Wit R, van der, Velden J, Burger C, et al. First results of triple-modality treatment combining radiotherapy, chemotherapy, and hyperthermia for the treatment of patients with stage IIB, III, and IVA cervical carcinoma. Cancer 2005; 104: 763–770

 PubMed Web of Science ®Google Scholar

Sreenivasa G, Hildebrandt B, Kummel S, Jungnickel K, Cho CH, Tilly W, Bohmer D, Budach V, Felix R, Wust P. Radiochemotherapy combined with regional pelvic hyperthermia induces high response and resectability rates in patients with nonresectable cervical cancer >/=FIGO IIB ‘bulky’. Int J Radiat Oncol Biol Phys 2006; 66: 1159–1167

 PubMed Web of Science ®Google Scholar

Herman TS, Teicher BA. Sequencing of trimodality therapy [cis-diamminedichloroplatinum(II)/hyperthermia/radiation] as determined by tumor growth delay and tumor cell survival in the FSaIIC fibrosarcoma. Cancer Res 1988; 48: 2693–2697

 PubMed Web of Science ®Google Scholar

Pfeffer MR, Teicher BA, Holden SA, al Achi A, Herman TS. The interaction of cisplatin plus etoposide with radiation +/− hyperthermia. Int J Radiat Oncol Biol Phys 1990; 19: 1439–1447

 PubMed Web of Science ®Google Scholar

Overgaard J, Radacic MM, Grau C. Interaction of hyperthermia and cis-diamminedichloroplatinum(II) alone or combined with radiation in a C3H mammary carcinoma in vivo. Cancer Res 1991; 51: 707–711

 PubMed Web of Science ®Google Scholar

Herman TS, Teicher BA, Holden SA, Pfeffer MR, Jones SM. Addition of 2-nitroimidazole radiosensitizers to cis-diamminedichloroplatinum(II) with radiation and with or without hyperthermia in the murine FSaIIC fibrosarcoma. Cancer Res 1990; 50: 2734–2740

 PubMed Web of Science ®Google Scholar

Rao BS, Devi PU. Response of mouse sarcoma-180 to cis-platin in combination with radiation & hyperthermia. Indian J Med Res 1996; 103: 315–322

 PubMedGoogle Scholar

Ressel A, Schmitt O, Weiss C, Feyerabend T. Therapeutic outcome and side-effects after radiotherapy, chemotherapy and/or hyperthermia treatment of head and neck tumour xenografts. Eur J Cancer 2002; 38: 594–601

 PubMedGoogle Scholar

Raaphorst GP, Yang H, Wilkins DE, Ng CE. Cisplatin, hyperthermia and radiation treatment in human cisplatin-sensitive and resistant glioma cell lines. Int J Hyperthermia 1996; 12: 801–812

 PubMed Web of Science ®Google Scholar

Raaphorst GP, Miao J, Ng CE. Cisplatin and mild hyperthermia in radiosensitization to low dose rate irradiation in human ovarian carcinoma cells. Anticancer Res 1997; 17: 3469–3472

 PubMedGoogle Scholar

Raaphorst GP, Miao J, Stewart D, Ng CE. Interactions of mild hyperthermia, cisplatin and split dose irradiation in human ovarian carcinoma cells. Cancer Chemother Pharmacol 1998; 41: 491–496

 PubMed Web of Science ®Google Scholar

Raaphorst GP, Maio J, Ng CE, Stewart DJ. Concomitant treatment with mild hyperthermia, cisplatin and low dose-rate irradiation in human ovarian cancer cells sensitive and resistant to cisplatin. Oncol Rep 1998; 5: 971–977

 PubMed Web of Science ®Google Scholar

Bergs JWJ, Haveman J, ten Cate R, Medema JP, Franken NAP, van Bree C. Effect of 41°C and 43°C on cisplatin-radiosensitization in two human carcinoma cell lines with different sensitivities for cisplatin. Oncol Rep, in press

 Google Scholar