Is CEM43 still a relevant thermal dose parameter for hyperthermia treatment monitoring?

Figures & data

Figure 1. Illustration of the association between number of (A) interstitial measurement points and thermal dose CEM43°CT90_tumour (Spearman’s rank correlation −0.64, p < 1e–10) and (B) tumour maximum diameter and thermal dose as total CEM43°CT90_tumour (Spearman’s rank correlation −0.70, p < 1e–6) in 72 patients with loco-regional breast cancer treated with superficial hyperthermia applied using 434 MHz microwaves. Picture from De Bruijne et al. [22], with permission.

Figure 2. Graphical representation of biological and physiological mechanisms involved in hyperthermia and the range in which they occur. The colour indicates the strength of the effect: blue is low, red is high. Blood flow and oxygenation start to increase at low temperatures, reach a maximum and decrease again when the temperature passes the thermal threshold for stasis (blue→ red →blue). White means unknown.

Table 1. Relation of CEM43 with response.

Heat effect	CEM43 relation	Remarks*	Reference no.
Cell cytotoxicity
Single fraction	Yes	Different slopes in CEM43 with a breakpoint between 42–44 °C	24,26–33
		• R = 0.5 for T > 43 °C • R = 0.25 for T ≤ 43 °C
Duration of exposure  Multiple fractions	Yes & No Yes & No	In cell cultures thermotolerance occurs for T < 44 °C and long exposure times (120 min)
Time interval between fractions	No	Thermotolerance disappear after 72 h
Degradation of DNA repair		Based on knowledge for response of BRCA2 on heat exposure		3,35–38
Single fraction	Yes	Dependence on temperature and time has been demonstrated
Multiple fractions	?	?
Duration of BRCA2 reduction	?	Addition of a HSP90 inhibiter prolongs time of reduced BRCA2 levels
Thermal radiosensitisation			27,28,33,34
Single fraction	Yes	For T > 42 °C
Multiple fractions	Yes
Time interval between   radiotherapy and   hyperthermia	No	Maximal enhancement with simultaneous heat and radiation With sequential heat and radiation enhancement decrease with increasing interval and disappears fully after 2–4 h
Tumour blood flow changes		Complex interaction	23,39–50,54–57
Single fraction  Duration of exposure	Yes Yes	Mild heating T ≤ 43 °C blood flow increases High heating T > 43 °C blood flow decreases Vascular stasis start to occur at CEM43 = 60–120 min Short heating t < 30 min blood flow increase Long heating t ∼ 60 min blood flow decrease
Multiple fractions	Yes?	A second heating 16, 24 and 48 h after the first heating may  enhance tumour blood flow. Effect depends on thermal dose of  2nd heat fraction.
		At higher CEM43 values tumour blood flow drops and loses its ability  to respond to a blood flow increase
Duration of perfusion change	Yes?	Duration dependent on thermal dose; increased perfusion may last as  long as 24 h
Normal tissue blood flow changes  Single fraction	Yes	Complex interaction, higher temperatures needed to induce blood  flow effect 42 °C < T < 45 °C blood flow increases T > 45 °C blood flow may decrease	41,42,46,61,65–69
		Vascular stasis start to occur at T = 45–47 °C
Duration of exposure	Yes	Short heating t < 60 min blood flow increase Long heating t ∼ 120 min blood flow decrease
Multiple fractions	Yes?	A second heating 16, 24 or 48 h after the first heating may enhance  normal tissue blood flow. Effect depends on thermal dose of second  heat fraction. Initial increase of blood flow on thermal load becomes, smaller with subsequent heat fractions, but basal normal tissue blood flow is slowly increasing, improving ratio tumour over normal tissue blood flow?
Duration of perfusion change	?	?	53
Oxygenation	Yes	Change in oxygenation parallels the change in blood flow	48–52
	?	Hyperthermia affect oxygen consumption	39,50,53, 58,59

*Values mentioned vary between tumour tissue type and species.

De Bruijne M, van der Holt B, van Rhoon GC, van der Zee J. Evaluation of CEM43T90 thermal dose in superficial hyperthermia. A retrospective analysis. Strahlenther Onkol 2010;186:436–43

 PubMed Web of Science ®Google Scholar

Dewey WC. Arrhenius relationships from the molecule and cell to the clinic. Int J Hyperthermia 1994;10:457–83

 PubMed Web of Science ®Google Scholar

Krawczyk PM, Eppink B, Essers J, Stap J, Rodermond HM, Odijk H, et al. Temperature-controlled induction of BRCA2 degradation and homologous recombination deficiency sensitizes cancer cells to PARP-1 inhibition. Proc Natl Acad Sci 2011;108:9851–6

 PubMed Web of Science ®Google Scholar

Field SB, Morris CC. The relationship between heating time and temperature: its relevance to clinical hyperthermia. Radiother Oncol 1983;1:179–86

 PubMedGoogle Scholar

Dewey WC, Hopwood LE, Sapareto SA, Gerweck LE. Cellular responses to combinations of hyperthermia and radiation. Radiology 1977;123:463–74

 PubMed Web of Science ®Google Scholar

Westra A. De invloed van straling op het vermogen tot proliferatie van in vitro gekweekte zoogdiercellen (The inpact of radiation on the proliferation potential of in vitro grown mammalian cells). PhD thesis, University of Amsterdam, 1971

 Google Scholar

Horsman MR, Overgaard J. Hyperthermia: a potent enhancer of radiotherapy. Clin Oncol 2007;19:418–26

 PubMed Web of Science ®Google Scholar

Field SB, Raaphorst GP. Thermal dose. In: Field SB, Hand JW, editors. An Introduction to the Practical Aspects of Clinical Hyperthermia. London: Taylor & Francis; 1990. pp 69–76

 Google Scholar

Lokshina AM, Song CW, Rhee JG, Levitt SH. Effect of fractionated heating on the blood flow in normal tissues. Int J Hyperthermia 1985;1:117–29

 PubMedGoogle Scholar

Song CW, Patten MS, Chelstrom LM, Rhee JG, Levitt SH. Effect of multiple heatings on the blood flow in RIF-1 tumours, skin and muscle of C3H mice. Int J Hyperthermia 1987;3:535–45

 PubMed Web of Science ®Google Scholar

Reinhold HS, Endrich B. Tumour microcirculation as a target for hyperthermia. Int J Hyperthermia 1986;2:111–37

 PubMedGoogle Scholar

Dewhirst MW, Sim DA, Gross J, Kundrat MA. Effect of heating rate and normal tissue microcirculatory function. In: Overgaard J, ed. Hyperthermic Oncology, Vol1. London: Taylor & Francis; 1984. pp 177–80

 Google Scholar

Vaupel P, Kelleher DK. Pathophysiological and vascular characteristic of tumours and their importance for hyperthermia: heterogeneity is the key issue. Int J Hyperthermia 2010;26:211–23

 PubMed Web of Science ®Google Scholar

Vujaskovic Z, Song CW. Physiological mechanisms underlying heat-induced radiosensitization. Int J Hyperthermia 2004;20:163–74

 PubMed Web of Science ®Google Scholar

Horsman MR, Overgaard J. Can mild hyperthermia improve tumor oxygenation? Int J Hyperthermia 1997;13:141–7

 PubMed Web of Science ®Google Scholar

Moon EJ, Sonveaux P, Porporato PE, Danhier P, Gallez B, Batinic-Haberle I, et al. NADPH oxidase-mediated reactive oxygen species production activates hypoxia-inducible factor-1 (HIF-1) via the ERK pathway after hyperthermia treatment. PNAS 2010;107:20477–82

 PubMed Web of Science ®Google Scholar

Secomb TW, Hsu R, Ong ET, Gross JF, Dewhirst MW. Analysis of the effects of oxygen supply and demand on hypoxic fraction in tumors. Acta Oncologica 1995;34:313–16

 PubMed Web of Science ®Google Scholar