Imaging tumour physiology and vasculature to predict and assess response to heat

International Journal of Hyperthermia

Volumn 26, Issue 3, 2010, Pages 264-272

  Hokland, Steffen L ^a   Nielsen, Thomas ^a,b   Busk, Morten ^a   Horsman, Michael R ^a  

^a AARHUS UNIVERSITY HOSPITAL   (Denmark)

^b AARHUS UNIVERSITY   (Denmark)

Author keywords

CT; Hypoxia; Imaging; Metabolism; MRI; Perfusion effects; PET; PH; Physiological effects of hyperthermia; Redox

Indexed keywords

CARBONATE DEHYDRATASE IX;

BIOENERGY; CELL DAMAGE; CELL HYPOXIA; COMPUTER ASSISTED TOMOGRAPHY; HEAT; HEAT TOLERANCE; HUMAN; HYPERTHERMIC THERAPY; MICROENVIRONMENT; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; OXYGENATION; PATHOPHYSIOLOGY; PH MEASUREMENT; POSITRON EMISSION TOMOGRAPHY; REVIEW; TUMOR VASCULARIZATION;

ANOXIA; HUMANS; HYPERTHERMIA, INDUCED; MAGNETIC RESONANCE IMAGING; MICROCIRCULATION; NEOPLASMS; POSITRON-EMISSION TOMOGRAPHY;

EID: 77951112833     PISSN: 02656736     EISSN: 14645157     Source Type: Journal    
DOI: 10.3109/02656730903585982     Document Type: Review

References (101)

1. Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med 1971;285:1182-1186.
2. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002;29:15-18.
3. Vaupel P. Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol 2004;14:198-206.
4. Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: A review. Cancer Research 1989;49:6449-6465.
5. Gillies RJ, Schornack PA, Secomb TW, Raghunand N. Causes and effects of heterogeneous perfusion in tumors. Neoplasia 1999;1:197-207.
6. Moulder JE, Rockwell S. Tumor hypoxia: Its impact on cancer therapy. Cancer Metastasis Rev 1987;5:313-341.
7. Vaupel P, Harrison L. Tumor hypoxia: Causative factors, compensatory mechanisms, and cellular response. Oncologist 2004;9:S4-S9.
8. Jain RK, Grantham FH, Gullino PM. Blood flow and heat transfer in Walker 256 mammary carcinoma. J Natl Cancer Inst 1979;62:927-933.
9. Patterson J, Strang R. The role of blood flow in hyperthermia. Int J Radiat Oncol Biol Phys 1979;5:235-241.
10. Gerweck LE, Nygaard TG, Burlett M. Response of cells to hyperthermia under acute and chronic hypoxic conditions. Cancer Res 1979;39:966-972.
11. Overgaard J, Bichel P. The influence of hypoxia and acidity on the hyperthermic response of malignant cells in vitro. Radiology 1977;123:511-514.
12. Overgaard J, Nielsen OS. The role of tissue environmental factors on the kinetics and morphology of tumor cells exposed to hyperthermia. Ann NY Acad Sci 1980;335:254-280.
13. Thrall DE, Gillette EL, Dewey WC. Effect of heat and ionizing radiation on normal and neoplastic tissue of the C3H mouse. Radiat Res 1975;63:363-377.
14. Hill SA, Denekamp J. The effect of vascular occlusion on the thermal sensitization of a mouse tumour. Br J Radiol 1978;51:997-1002.
15. Horsman MR, Christensen KL, Overgaard J. Hydralazine-induced enhancement of hyperthermic damage in a C3H mammary carcinoma in vivo. Int J Hyperthermia 1989;5:123-136.
16. Prescott DM, Samulski TV, Dewhirst MW, Page RL, Thrall DE, Dodge RK, Oleson JR. Use of nitroprusside to increase tissue temperature during local hyperthermia in normal and tumor-bearing dogs. Int J Radiat Oncol BiolPhys 1992;23:377-385.
17. Urano M, Montoya V, Booth A. Effect of hyperglycemia on the thermal response of murine normal and tumor tissues. Cancer Res 1983;43:453-455. (Pubitemid 13193828)
18. Horsman MR, Murata R. Combination of vascular targeting agents with thermal or radiation therapy. Int J Radiat Oncol Biol Phys 2002;54:1518-1523.
19. Horsman MR. Tissue physiology and the response to heat. Int J Hyperthermia 2006;22:197-203.
20. Horsman MR. Angiogenesis and vascular targeting: Relevance for hyperthermia. Int J Hyperthermia 2008;24:57-65.
21. Horsman MR, Murata R, Breidahl T, Nielsen FU, Maxwell RJ, Stodkiled-Jorgensen H, Overgaard J. Combretastatins novel vascular targeting drugs for improving anti-cancer therapy. Combretastatins and conventional therapy. Adv Exp Med Biol 2000;476:311-323.
22. Murata R, Overgaard J, Horsman MR. Combretastatin A-4 disodium phosphate: A vascular targeting agent that improves that improves the anti-tumor effects of hyperthermia, radiation, and mild thermoradiotherapy. Int J Radiat Oncol Biol Phys 2001;51:1018-1024.
23. Hokland SL, Horsman MR. The new vascular disrupting agent combretastatin-A1-disodium-phosphate (OXi4503) enhances tumour response to mild hyperthermia and thermoradiosensitization. Int J Hyperthermia 2007;23:599-606.
24. Vaupel P, Kallinowski F. Physiological effects of hyperthermia. In: Streffer C, editor. Recent results in cancer research. Heidelberg, Berlin: Springer; 1987. pp 71-109.
25. Weissleder R, Mahmood U. Molecular imaging. Radiology 2001;219:316-333.
26. Appelgren LK. Methods of recording tumor blood flow. In: Peterson H-I, editor. Tumor blood circulation: Angiogenesis, vascular morphology and blood flow of experimental and human tumors. Boca Raton: CRC Press; 1979. pp 87-101.
27. Vaupel P, Okunieff P, Kluge M. Response of tumour red blood cell flux to hyperthermia and/or hyperglycaemia. Int J Hyperthermia 1989;5:199-210.
28. Brix G, Semmler W, Port RE, Schad LR, Layer G, Lorenz WJ. Pharmacokinetic parameters in CNS Gd-DTPA enhanced MR imaging. J Comput Assist Tomog 1991; 15:621-628.
29. Larsson HB, Stubgaard M, Frederiksen JL, Jensen M, Henriksen O, Paulson OB. Quantitation of blood-brain barrier defect by magnetic resonance imaging and gadolinium-DTPA in patients with multiple sclerosis and brain tumors. Magn Reson Med 1990;16:117-131.
30. Tofts PS, Kermode AG. Measurement of the blood-brain barrier permeability and leakage space using dynamic MR imaging. Magn Reson Med 1991;17:357-367.
31. Lyng H, Vorren AO, Sundfor K, Taksdal I, Lien HH, Kaalhus O, Rofstad EK. Assessment of tumor oxygenation in human cervical carcinoma by use of dynamic Gd-DTPA-enhanced MR imaging. J Magn Reson Imag 2001;14:750-756.
32. Leach MO, Brindle KM, Evelhoch JL, Griffiths JR, Horsman MR, Jackson A, Jayson G, Judson IR, Knopp MV, Maxwell RJ. Assessment of antiangiogenic and antivascular therapeutics using MRI: recommendations for appropriate methodology for clinical trials. Brit J Radiol 2003;76:S87-S91.
33. Evelhoch JL, LoRusso PM, He Z, DelProposto Z, Polin L, Corbett TH, Langmuir P, Wheeler C, Stone A, Leadbetter J. Magnetic resonance imaging measurements of the response of murine and human tumors to the vascular-targeting agent ZD6126. Clin Cancer Res 2004;10:3650-3657.
34. Galbraith SM, Lodge MA, Taylor NJ, Rustin GJ, Bentzen S, Stirling JJ, Padhani AR. Reproducibility of dynamic contrastenhanced MRI in human muscle and tumours: Comparison of quantitative and semi-quantitative analysis. NMR Biomed 2002;15:132-142.
35. Tofts PS, Brix G, Buckley DL, Evelhoch JL, Henderson E, Knopp MV, Larsson HB, Lee TY, Mayr NA, Parker GJ, et al. Estimating kinetic parameters from dynamic contrastenhanced T(1)-weighted MRI of a diffusable tracer: Standardized quantities and symbols. J Magn Reson Imag 1999;10:223-232.
36. Kety SS. Blood-exchange methods. Theory of blood-tissue exchange and its application to measurement of blood flow. Methods Med Res 1960;8:223-227.
37. Lawrence KSS, Lee TY. An adiabatic approximation to the tissue homogeneity model for water exchange in the brain: I. Theoretical derivation. J Cereb Blood Flow Metab 1998;18:1365-1377.
38. Boxerman JL, Hamberg LM, Rosen BR, Weisskoff RM. MR contrast due to intravascular magnetic susceptibility perturbations. Magn Reson Med 1995;34:555-566.
39. Kjolby BF, Ostergaard L, Kiselev VG. Theoretical model of intravascular paramagnetic tracers effect on tissue relaxation. Magn Reson Med 2006;56:187-197.
40. Ostergaard L, Sorensen AG, Kwong KK, Weisskoff RM, Gyldensted C, Rosen BR. High resolution measurement of cerebral blood flow using intravascular tracer bolus passages. Part II: Experimental comparison and preliminary results. Magn Reson Med 1996;36:726-736. (Pubitemid 26376711)
41. Dennie J, Mandeville JB, Boxerman JL, Packard SD, Rosen BR, Weisskoff RM. NMR imaging of changes in vascular morphology due to tumor angiogenesis. Magn Reson Med 1998;40:793-799.
42. Kiselev VG, Strecker R, Ziyeh S, Speck O, Hennig J. Vessel size imaging in humans. Magn Reson Med 2005;53:553-563.
43. Tropres I, Lamalle L, Peoc'h M, Farion R, Usson Y, Decorps M, Remy C. In vivo assessment of tumoral angiogenesis. Magn Reson Med 2004;51:533-541.
44. Quarles CC, Schmainda KM. Assessment of the morphological and functional effects of the anti-angiogenic agent SU11657 on 9L gliosarcoma vasculature using dynamic susceptibility contrast MRI. Magn Reson Med 2007;57: 680-687.
45. Robinson SP, Rijken PF, Howe FA, McSheehy PM, Van Der Sanden BP, Heerschap A, Stubbs M, Van Der Kogel AJ, Griffiths JR. Tumor vascular architecture and function evaluated by non-invasive susceptibility MRI methods and immunohistochemistry. J Magn Reson Imag 2003;17: 445-454.
46. Abramovitch R, Dafni H, Smouha E, Benjamin LE, Neeman M. In vivo prediction of vascular susceptibility to vascular susceptibility endothelial growth factor withdrawal: Magnetic resonance imaging of C6 rat glioma in nude mice. Cancer Res 1999;59:5012-5016.
47. Kostourou V, Robinson SP, Cartwright JE, Whitley GS. Dimethylarginine dimethylaminohydrolase I enhances tumour growth and angiogenesis. Br J Cancer 2002;87:673-680.
48. Robinson SP, McIntyre DJ, Checkley D, Tessier JJ, Howe FA, Griffiths JR, Ashton SE, Ryan AJ, Blakey DC, Waterton JC. Tumour dose response to the antivascular agent ZD6126 assessed by magnetic resonance imaging. Br J Cancer 2003;88:1592-1597.
49. Lodge MA, Jacene HA, Pili R, Wahl RL. Reproducibility of tumor blood flow quantification with 15O-water PET. J Nucl Med 2008;49:1620-1627.
50. Komar G, Seppanen M, Eskola O, Lindholm P, Gronroos TJ, Forsback S, Sipila H, Evans SM, Solin O, Minn H. 18F-EF5: A new PET tracer for imaging hypoxia in head and neck cancer. J Nucl Med 2008;49:1944-1951.
51. Ludemann L, Wust P, Gellermann J. Perfusion measurement using DCE-MRI: Implications for hyperthermia. Int J Hyperthermia 2008;24:91-96.
52. Ludemann L, Sreenivasa G, Amthauer H, Michel R, Gellermann J, Wust P. Use of H(2) (15)O-PET for investigating perfusion changes in pelvic tumors due to regional hyperthermia. Int J Hyperthermia 2009;25:299-308.
53. Viglianti BL, Lora-Michiels M, Poulson JM, Lan L, Yu D, Sanders L, Craciunescu O, Vujaskovic Z, Thrall DE, Macfall J, et al. Dynamic contrast-enhanced magnetic resonance imaging as a predictor of clinical outcome in canine spontaneous soft tissue sarcomas treated with thermoradiotherapy. Clin Cancer Res 2009;15:4993-5001.
54. Craciunescu OI, Blackwell KL, Jones EL, Macfall JR, Yu D, Vujaskovic Z, Wong TZ, Liotcheva V, E LR, Prosnitz LR, et al. DCE-MRI parameters have potential to predict response of locally advanced breast cancer patients to neoadjuvant chemotherapy and hyperthermia: A pilot study. Int J Hyperthermia 2009:1-11.
55. Park MS, Klotz E, Kim MJ, Song SY, Park SW, Cha SW, Lim JS, Seong J, Chung JB, Kim KW. Perfusion CT: Noninvasive surrogate marker for stratification of pancreatic cancer response to concurrent chemo- and radiation therapy. Radiology 2009;250:110-117.
56. Delorme S, Krix M. Contrast-enhanced ultrasound for examining tumor biology. Cancer Imaging 2006;6: 148-152.
57. Shakil A, Osborn JL, Song CW. Changes in oxygenation status and blood flow in a rat tumor model by mild temperature hyperthermia. Int J Radiat Oncol Biol Phys 1999;43:859-865.
58. Horsman MR, Overgaard J. Can mild hyperthermia improve tumour oxygenation? Int J Hyperthermia 1997;13:141-147.
59. Iwata K, Shakil A, Hur WJ, Makepeace CM, Griffin RJ, Song CW. Tumour pO2 can be increased markedly by mild hyperthermia. Br J Cancer Suppl 1996;27:S217-221. (Pubitemid 26237965)
60. Kallinowski F, Zander R, Hoeckel M, Vaupel P. Tumor tissue oxygenation as evaluated by computerized-pO2-histography. Int J Radiat Oncol Biol Phys 1990;19:953-961.
61. Song CW, Shakil A, Osborn JL, Iwata K. Tumour oxygenation is increased by hyperthermia at mild temperatures. Int J Hyperthermia 1996;12:367-373. (Pubitemid 26158699)
62. Okajima K, Griffin RJ, Iwata K, Shakil A, Song CW. Tumor oxygenation after mild-temperature hyperthermia in combination with carbogen breathing: Dependence on heat dose and tumor type. Radiat Res 1998;149:294-299.
63. Thomas SR. In: Partain CL, Price RR, Patton JA, Kulkarni MV, and James AEJ, editors. The biomedical applications of Fluorine-19 NMR. London: W.B. Saunders; 1988.
64. Yu JX, Kodibagkar VD, Cui W, Mason RP. 19F: A versatile reporter for non-invasive physiology and pharmacology using magnetic resonance. Curr Med Chem 2005;12:819-848.
65. Mason RP, Rodbumrung W, Antich PP. Hexafluorobenzene: A sensitive 19F NMR indicator of tumor oxygenation. NMR Biomed 1996;9:125-134.
66. Hunjan S, Mason RP, Constantinescu A, Peschke P, Hahn EW, Antich PP. Regional tumor oximetry: 19F NMR spectroscopy of hexafluorobenzene. Int J Radiat Oncol Biol Phys 1998;41:161-171.
67. Le D, Mason RP, Hunjan S, Constantinescu A, Barker BR, Antich PP. Regional tumor oxygen dynamics: 19F PBSR EPI of hexafluorobenzene. Magn Reson Imag 1997;15:971-981.
68. Mason RP, Constantinescu A, Hunjan S, Le D, Hahn EW, Antich PP, Blum C, Peschke P. Regional tumor oxygenation and measurement of dynamic changes. Radiat Res 1999;152: 239-249.
69. Xia M, Kodibagkar V, Liu H, Mason RP. Tumour oxygen dynamics measured simultaneously by near-infrared spectroscopy and 19F magnetic resonance imaging in rats. Phys Med Biol 2006;51:45-60.
70. Wang Z, Su MY, Nalcioglu O. Applications of dynamic contrast enhanced MRI in oncology: Measurement of tumor oxygen tension. Technol Cancer Res Treat 2002;1:29-38.
71. Rasey JS, Nelson NJ, Chin L, Evans ML, Grunbaum Z. Characteristics of the binding of labeled fluoromisonidazole in cells in vitro. Radiat Res 1990;122:301-308.
72. Busk M, Horsman MR, Jakobsen S, Bussink J, van der Kogel A, Overgaard J. Cellular uptake of PET tracers of glucose metabolism and hypoxia and their linkage. Eur J Nucl Med Mol Imag 2008;35:2294-2303.
73. Busk M, Horsman MR, Overgaard J. Resolution in PET hypoxia imaging: Voxel size matters. Acta Oncol 2008;47:1201-1210.
74. Sun X, Li XF, Russell J, Xing L, Urano M, Li GC, Humm JL, Ling CC. Changes in tumor hypoxia induced by mild temperature hyperthermia as assessed by dual-tracer immunohistochemistry. Radiother Oncol 2008;88:269-276.
75. Lewis JS, McCarthy DW, McCarthy TJ, Fujibayashi Y, Welch MJ. Evaluation of 64Cu-ATSM in vitro and in vivo in a hypoxic tumor model. J Nucl Med 1999;40:177-183.
76. Dence CS, Ponde DE, Welch MJ, Lewis JS. Autoradiographic and small-animal PET comparisons between (18)F-FMISO, (18)F-FDG, (18)F-FLT and the hypoxic selective (64)Cu-ATSM in a rodent model of cancer. Nucl Med Biol 2008;35:713-720.
77. Myerson RJ, Singh AK, Bigott HM, Cha B, Engelbach JA, Kim J, Lamoreaux WT, Moros E, Novak P, Sharp TL, et al. Monitoring the effect of mild hyperthermia on tumour hypoxia by Cu-ATSM PET scanning. Int J Hyperthermia 2006;22:93-115.
78. Vavere AL, Lewis JS. Examining the relationship between Cu-ATSM hypoxia selectivity and fatty acid synthase expression in human prostate cancer cell lines. Nucl Med Biol 2008;35:273-279.
79. O'Donoghue JA, Zanzonico P, Pugachev A, Wen B, Smith- Jones P, Cai S, Burnazi E, Finn RD, Burgman P, Ruan S, et al. Assessment of regional tumor hypoxia using 18F-fluoromisonidazole and 64Cu(II)-diacetylbis( N4-methylthiosemicarbazone) positron emission tomography: Comparative study featuring microPET imaging, Po2 probe measurement, autoradiography, and fluorescent microscopy in the R3327-AT and FaDu rat tumor models. Int J Radiat Oncol Biol Phys 2005;61:1493-1502.
80. Matsumoto K, Szajek L, Krishna MC, Cook JA, Seidel J, Grimes K, Carson J, Sowers AL, English S, Green MV, et al. The influence of tumor oxygenation on hypoxia imaging in murine squamous cell carcinoma using [64Cu]Cu-ATSM or [18F]Fluoromisonidazole positron emission tomography. Int J Oncol 2007;30:873-881.
81. Chapman JD, Coia LR, Stobbe CC, Engelhardt EL, Fenning MC, Schneider RF. Prediction of tumour hypoxia and radioresistance with nuclear medicine markers. Br J Cancer Suppl 1996;27:S204-S208.
82. Parliament MB, Chapman JD, Urtasun RC, McEwan AJ, Golberg L, Mercer JR, Mannan RH, Wiebe LI. Non-invasive assessment of human tumour hypoxia with 123I-iodoazomycin arabinoside: Preliminary report of a clinical study. Br J Cancer 1992;65:90-95.
83. Urtasun RC, Parliament MB, McEwan AJ, Mercer JR, Mannan RH, Wiebe LI, Morin C, Chapman JD. Measurement of hypoxia in human tumours by non-invasive spect imaging of iodoazomycin arabinoside. Br J Cancer Suppl 1996;27:S209-S212.
84. Liu H, Song Y, Worden KL, Jiang X, Constantinescu A, Mason RP. Noninvasive investigation of blood oxygenation dynamics of tumors by near-infrared spectroscopy. Appl Opt 2000;39:5231-5243.
85. Elas M, Williams BB, Parasca A, Mailer C, Pelizzari CA, Lewis MA, River JN, Karczmar GS, Barth ED, Halpern HJ. Quantitative tumor oxymetric images from 4D electron paramagnetic resonance imaging (EPRI): Methodology and comparison with blood oxygen level-dependent (BOLD) MRI. Magn Reson Med 2003;49:682-691.
86. Gillies RJ, Raghunand N, Garcia-Martin ML, Gatenby RA. pH imaging. A review of pH measurement methods and applications in cancers. IEEE Eng Med Biol Mag 2004;23:57-64.
87. Van Der Toorn A, Sykova E, Dijkhuizen RM, Vorisek I, Vargova L, Skobisova E, Van Lookeren Campagne M, Reese T, Nicolay K. Dynamic changes in water ADC, energy metabolism, extracellular space volume, and tortuosity in neonatal rat brain during global ischemia. Magn Reson Med 1996;36:52-60.
88. Remy C, Albrand JP, Benabid AL, Decorps M, Jacrot M, Riondel J, Foray MF. In vivo 31P nuclear magnetic resonance studies of T1 and T2 relaxation times in rat brain and in rat brain tumors implanted to nude mice. Magn Reson Med 1987;4:144-152.
89. Vaupel P, Okunieff P, Neuringer LJ. In vivo 31P-NMR spectroscopy of murine tumours before and after localized hyperthermia. Int J Hyperthermia 1990;6:15-31.
90. Sijens PE, Bovee WM, Koole P, Schipper J. Phosphorus NMR study of the response of a murine tumour to hyperthermia as a function of treatment time and temperature. Int J Hyperthermia 1989;5:351-357.
91. Ward KM, Balaban RS. Determination of pH using water protons and chemical exchange dependent saturation transfer (CEST). Magn Reson Med 2000;44:799-802.
92. Lawrentschuk N, Lee FT, Jones G, Rigopoulos A, Mountain A, O'Keefe G, Papenfuss AT, Bolton DM, Davis ID, Scott AM. Investigation of hypoxia and carbonic anhydrase IX expression in a renal cell carcinoma xenograft model with oxygen tension measurements and (124)I-cG250 PET/CT. Urol Oncol 2009.
93. Kelleher DK, Engel T, Vaupel PW. Changes in microregional perfusion, oxygenation, ATP and lactate distribution in subcutaneous rat tumours upon water-filtered IR-A hyperthermia. Int J Hyperthermia 1995;11:241-255.
94. Nielsen FU, Daugaard P, Bentzen L, Stodkilde-Jorgensen H, Overgaard J, Horsman MR, et al. Effect of changing tumor oxygenation on glycolytic metabolism in a murine C3H mammary carcinoma assessed by in vivo nuclear magnetic resonance spectroscopy. Cancer Res 2001;61:5318-5325.
95. Hoh CK. Clinical use of FDG PET. Nucl Med Biol 2007;34:737-742.
96. Weber WA. Assessing tumor response to therapy. J Nucl Med 2009;50:S1-10.
97. Herrmann K, Krause BJ, Bundschuh RA, Dechow T, Schwaiger M. Monitoring response to therapeutic interventions in patients with cancer. Semin Nucl Med 2009;39:210-232.
98. Ishii K, Hosono MN, Wada Y, Maeda M, Kondo S, Takada Y, Tada T, Okamura T, Watanabe Y, Inoue Y. Usefulness of FDG-microPET for early evaluation of therapeutic effects on VX2 rabbit carcinoma. Ann Nucl Med 2006;20:123-130.
99. Westerterp M, Omloo JM, Sloof GW, Hulshof MC, Hoekstra OS, Crezee H, Boellaard R, Vervenne WL, ten Kate FJ, van Lanschot JJ. Monitoring of response to pre-operative chemoradiation in combination with hyperthermia in oesophageal cancer by FDG-PET. Int J Hyperthermia 2006;22:149-160.
100. Mueller-Klieser W, Walenta S, Paschen W, Kallinowski F, Vaupel P. Metabolic imaging in microregions of tumors and normal tissues with bioluminescence and photon counting. J Natl Cancer Inst 1988;80:842-848.
101. Horsman MR, Overgaard J. Hyperthermia: A potent enhancer of radiotherapy. Clin Oncol 2007;19:418-426.