Kosin Med J.  2024 Sep;39(3):160-168. 10.7180/kmj.24.127.

Current understanding of modulated electro-hyperthermia in cancer treatment

• Kim S
• Yu J
• Kang J
• Kim Y
• Ko TY

• KMID: 2559403
• DOI: http://doi.org/10.7180/kmj.24.127

Abstract

Traditional hyperthermia involves increasing the temperature at the tumor site to above 39 ℃, inducing death in cancer cells. Although hyperthermia is an effective cancer treatment, its clinical application has decreased due to potential complications, including damage to surrounding normal tissue. In recent years, modulated electro-hyperthermia (mEHT) has emerged as an effective and safe treatment modality. mEHT selectively heats tumor cells to 42–43 °C, while reducing the average temperature in the treatment area, including the surrounding normal tissue, compared to conventional methods. Additionally, mEHT may be used in combination with systemic chemotherapy and radiation therapy in tumor treatment, providing a synergistic effect to increase efficacy. As chemotherapy and radiation therapy technologies advance, the application of combined mEHT may improve clinical outcomes. In this study, we review and discuss reports on the clinical outcomes of mEHT combined with chemotherapy and/or radiation therapy, which are established anticancer treatments.

Keyword

Cancer treatment; Combined treatments; Hyperthermia; Modulated electro-hyperthermia

Figure

• 

  Fig. 1. Mechanism of modulated electro-hyperthermia (mEHT).

Reference

References

1. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006; 355:11–20.

2. Schneider BJ, Ismaila N, Altorki N. Lung cancer surveillance after definitive curative-intent therapy: ASCO guideline summary. JCO Oncol Pract. 2020; 16:83–6.

3. Daly ME, Ismaila N, Decker RH, Higgins K, Owen D, Saxena A, et al. Radiation therapy for small-cell lung cancer: ASCO guideline endorsement of an ASTRO guideline. J Clin Oncol. 2021; 39:931–9.

4. Fiorentini G, Szasz A. Hyperthermia today: electric energy, a new opportunity in cancer treatment. J Cancer Res Ther. 2006; 2:41–6.

5. Andocs G, Szasz O, Szasz A. Oncothermia treatment of cancer: from the laboratory to clinic. Electromagn Biol Med. 2009; 28:148–65.

6. Roussakow SV. Clinical and economic evaluation of modulated electrohyperthermia concurrent to dose-dense temozolomide 21/28 days regimen in the treatment of recurrent glioblastoma: a retrospective analysis of a two-centre German cohort trial with systematic comparison and effect-to-treatment analysis. BMJ Open. 2017; 7:e017387.

7. Kirui DK, Koay EJ, Guo X, Cristini V, Shen H, Ferrari M. Tumor vascular permeabilization using localized mild hyperthermia to improve macromolecule transport. Nanomedicine. 2014; 10:1487–96.

8. Oei AL, Vriend LE, Krawczyk PM, Horsman MR, Franken NA, Crezee J. Targeting therapy-resistant cancer stem cells by hyperthermia. Int J Hyperthermia. 2017; 33:419–27.

9. Baronzio G, Gramaglia A, Fiorentini G. Hyperthermia and immunity: a brief overview. In Vivo. 2006; 20(6A):689–95.

10. Hildebrandt B, Wust P, Ahlers O, Dieing A, Sreenivasa G, Kerner T, et al. The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol. 2002; 43:33–56.

11. Kang G, Kim SE. How to write an original article in medicine and medical science. Kosin Med J. 2022; 37:96–101.

12. Kim DJ, Kil SY, Son J, Lee HS. How to conduct well-designed clinical research. Kosin Med J. 2022; 37:187–91.

13. Dewhirst MW, Viglianti BL, Lora-Michiels M, Hanson M, Hoopes PJ. Basic principles of thermal dosimetry and thermal thresholds for tissue damage from hyperthermia. Int J Hyperthermia. 2003; 19:267–94.

14. Griffin RJ, Dings RP, Jamshidi-Parsian A, Song CW. Mild temperature hyperthermia and radiation therapy: role of tumour vascular thermotolerance and relevant physiological factors. Int J Hyperthermia. 2010; 26:256–63.

15. Datta NR, Ordonez SG, Gaipl US, Paulides MM, Crezee H, Gellermann J, et al. Local hyperthermia combined with radiotherapy and-/or chemotherapy: recent advances and promises for the future. Cancer Treat Rev. 2015; 41:742–53.

16. Dong Y, Wu G. Analysis of short and long term therapeutic effects of radiofrequency hyperthermia combined with conformal radiotherapy in hepatocellular carcinoma. J BUON. 2016; 21:407–11.

17. Skandalakis GP, Rivera DR, Rizea CD, Bouras A, Jesu Raj JG, Bozec D, et al. Hyperthermia treatment advances for brain tumors. Int J Hyperthermia. 2020; 37:3–19.

18. Moeller BJ, Dewhirst MW. HIF-1 and tumour radiosensitivity. Br J Cancer. 2006; 95:1–5.

19. Kaur P, Hurwitz MD, Krishnan S, Asea A. Combined hyperthermia and radiotherapy for the treatment of cancer. Cancers (Basel). 2011; 3:3799–823.

20. Lee SY, Kim JH, Han YH, Cho DH. The effect of modulated electro-hyperthermia on temperature and blood flow in human cervical carcinoma. Int J Hyperthermia. 2018; 34:953–60.

21. Elming PB, Sorensen BS, Oei AL, Franken NA, Crezee J, Overgaard J, et al. Hyperthermia: the optimal treatment to overcome radiation resistant hypoxia. Cancers (Basel). 2019; 11:60.

22. Schneider CS, Woodworth GF, Vujaskovic Z, Mishra MV. Radiosensitization of high-grade gliomas through induced hyperthermia: review of clinical experience and the potential role of MR-guided focused ultrasound. Radiother Oncol. 2020; 142:43–51.

23. Hegyi G, Szigeti GP, Szasz A. Hyperthermia versus oncothermia: cellular effects in complementary cancer therapy. Evid Based Complement Alternat Med. 2013; 2013:672873.

24. Lee SY, Lee NR, Cho DH, Kim JS. Treatment outcome analysis of chemotherapy combined with modulated electro-hyperthermia compared with chemotherapy alone for recurrent cervical cancer, following irradiation. Oncol Lett. 2017; 14:73–8.

25. Gadaleta-Caldarola G, Infusino S, Galise I, Ranieri G, Vinciarelli G, Fazio V, et al. Sorafenib and locoregional deep electro-hyperthermia in advanced hepatocellular carcinoma: a phase II study. Oncol Lett. 2014; 8:1783–7.

26. Wismeth C, Dudel C, Pascher C, Ramm P, Pietsch T, Hirschmann B, et al. Transcranial electro-hyperthermia combined with alkylating chemotherapy in patients with relapsed high-grade gliomas: phase I clinical results. J Neurooncol. 2010; 98:395–405.

27. Kouloulias VE, Nikita KS, Kouvaris JR, Uzunoglu NK, Golematis VC, Papavasiliou CG, et al. Cytoreductive surgery combined with intraoperative chemo-hyperthermia and postoperative radiotherapy in the management of advanced pancreatic adenocarcinoma: feasibility aspects and efficacy. J Hepatobiliary Pancreat Surg. 2001; 8:564–70.

28. Herold Z, Szasz AM, Dank M. Evidence based tools to improve efficiency of currently administered oncotherapies for tumors of the hepatopancreatobiliary system. World J Gastrointest Oncol. 2021; 13:1109–20.

29. van der Horst A, Versteijne E, Besselink MG, Daams JG, Bulle EB, Bijlsma MF, et al. The clinical benefit of hyperthermia in pancreatic cancer: a systematic review. Int J Hyperthermia. 2018; 34:969–79.

30. Fiorentini G, Giovanis P, Rossi S, Dentico P, Paola R, Turrisi G, et al. A phase II clinical study on relapsed malignant gliomas treated with electro-hyperthermia. In Vivo. 2006; 20(6A):721–4.

31. Ohguri T, Imada H, Yahara K, Narisada H, Morioka T, Nakano K, et al. Concurrent chemoradiotherapy with gemcitabine plus regional hyperthermia for locally advanced pancreatic carcinoma: initial experience. Radiat Med. 2008; 26:587–96.

32. Bakshandeh-Bath A, Stoltz AS, Homann N, Wagner T, Stolting S, Peters SO. Preclinical and clinical aspects of carboplatin and gemcitabine combined with whole-body hyperthermia for pancreatic adenocarcinoma. Anticancer Res. 2009; 29:3069–77.

33. Yeo SG. Definitive radiotherapy with concurrent oncothermia for stage IIIB non-small-cell lung cancer: a case report. Exp Ther Med. 2015; 10:769–72.

34. Rao W, Deng ZS, Liu J. A review of hyperthermia combined with radiotherapy/chemotherapy on malignant tumors. Crit Rev Biomed Eng. 2010; 38:101–16.

35. Kampinga HH. Cell biological effects of hyperthermia alone or combined with radiation or drugs: a short introduction to newcomers in the field. Int J Hyperthermia. 2006; 22:191–6.

36. Datta NR, Puric E, Klingbiel D, Gomez S, Bodis S. Hyperthermia and radiation therapy in locoregional recurrent breast cancers: a systematic review and meta-analysis. Int J Radiat Oncol Biol Phys. 2016; 94:1073–87.

37. Loboda A, Smolanka I Sr, Orel VE, Syvak L, Golovko T, Dosenko I, et al. Efficacy of combination neoadjuvant chemotherapy and regional inductive moderate hyperthermia in the treatment of patients with locally advanced breast cancer. Technol Cancer Res Treat. 2020; 19:1533033820963599.

38. Klimanov MY, Syvak LA, Orel VE, Lavryk GV, Tarasenko TY, Orel VB, et al. Efficacy of combined regional inductive moderate hyperthermia and chemotherapy in patients with multiple liver metastases from breast cancer. Technol Cancer Res Treat. 2018; 17:1533033818806003.

39. Hu Y, Li Z, Mi DH, Cao N, Zu SW, Wen ZZ, et al. Chemoradiation combined with regional hyperthermia for advanced oesophageal cancer: a systematic review and meta-analysis. J Clin Pharm Ther. 2017; 42:155–64.

40. Kang M, Liu WQ, Qin YT, Wei ZX, Wang RS. Long-term efficacy of microwave hyperthermia combined with chemoradiotherapy in treatment of nasopharyngeal carcinoma with cervical lymph node metastases. Asian Pac J Cancer Prev. 2013; 14:7395–400.

41. Zhao C, Chen J, Yu B, Chen X. Improvement in quality of life in patients with nasopharyngeal carcinoma treated with non-invasive extracorporeal radiofrequency in combination with chemoradiotherapy. Int J Radiat Biol. 2014; 90:853–8.

42. Ren G, Ju H, Wu Y, Song H, Ma X, Ge M, et al. A multicenter randomized phase II trial of hyperthermia combined with TPF induction chemotherapy compared with TPF induction chemotherapy in locally advanced resectable oral squamous cell carcinoma. Int J Hyperthermia. 2021; 38:939–47.

43. Mitsumori M, Zeng ZF, Oliynychenko P, Park JH, Choi IB, Tatsuzaki H, et al. Regional hyperthermia combined with radiotherapy for locally advanced non-small cell lung cancers: a multi-institutional prospective randomized trial of the International Atomic Energy Agency. Int J Clin Oncol. 2007; 12:192–8.

44. Shen H, Li XD, Wu CP, Yin YM, Wang RS, Shu YQ. The regimen of gemcitabine and cisplatin combined with radio frequency hyperthermia for advanced non-small cell lung cancer: a phase II study. Int J Hyperthermia. 2011; 27:27–32.

45. Schulze T, Wust P, Gellermann J, Hildebrandt B, Riess H, Felix R, et al. Influence of neoadjuvant radiochemotherapy combined with hyperthermia on the quality of life in rectum cancer patients. Int J Hyperthermia. 2006; 22:301–18.

46. De Haas-Kock DF, Buijsen J, Pijls-Johannesma M, Lutgens L, Lammering G, van Mastrigt GA, et al. Concomitant hyperthermia and radiation therapy for treating locally advanced rectal cancer. Cochrane Database Syst Rev. 2009; (3):CD006269.

47. Issels RD, Lindner LH, Verweij J, Wessalowski R, Reichardt P, Wust P, et al. Effect of neoadjuvant chemotherapy plus regional hyperthermia on long-term outcomes among patients with localized high-risk soft tissue sarcoma: the EORTC 62961-ESHO 95 Randomized Clinical Trial. JAMA Oncol. 2018; 4:483–92.

48. Veltsista PD, Oberacker E, Ademaj A, Corradini S, Eckert F, Florcken A, et al. Hyperthermia in the treatment of high-risk soft tissue sarcomas: a systematic review. Int J Hyperthermia. 2023; 40:2236337.

49. Jones EL, Oleson JR, Prosnitz LR, Samulski TV, Vujaskovic Z, Yu D, et al. Randomized trial of hyperthermia and radiation for superficial tumors. J Clin Oncol. 2005; 23:3079–85.

50. Lutgens L, van der Zee J, Pijls-Johannesma M, De Haas-Kock DF, Buijsen J, Mastrigt GA, et al. Combined use of hyperthermia and radiation therapy for treating locally advanced cervix carcinoma. Cochrane Database Syst Rev. 2010; 2010:CD006377.

51. Datta NR, Rogers S, Klingbiel D, Gomez S, Puric E, Bodis S. Hyperthermia and radiotherapy with or without chemotherapy in locally advanced cervical cancer: a systematic review with conventional and network meta-analyses. Int J Hyperthermia. 2016; 32:809–21.

52. Minnaar CA, Maposa I, Kotzen JA, Baeyens A. Effects of modulated electro-hyperthermia (mEHT) on two and three year survival of locally advanced cervical cancer patients. Cancers (Basel). 2022; 14:656.

53. Yea JW, Park JW, Oh SA, Park J. Chemoradiotherapy with hyperthermia versus chemoradiotherapy alone in locally advanced cervical cancer: a systematic review and meta-analysis. Int J Hyperthermia. 2021; 38:1333–40.

54. van der Zee J, Gonzalez Gonzalez D, van Rhoon GC, van Dijk JD, van Putten WL, Hart AA. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Dutch Deep Hyperthermia Group. Lancet. 2000; 355:1119–25.

55. Chi MS, Yang KL, Chang YC, Ko HL, Lin YH, Huang SC, et al. Comparing the effectiveness of combined external beam radiation and hyperthermia versus external beam radiation alone in treating patients with painful bony metastases: a phase 3 prospective, randomized, controlled trial. Int J Radiat Oncol Biol Phys. 2018; 100:78–87.