LOCAL HYPERTHERMIA IN THE TREATMNET OF LOCALLY ADVANCED CERVICAL CANCER: CURRENT VIEW ON THE PROBLEM

The purpose of the study was to review available data on the combined use of local hyperthermia and chemotherapy/radiotherapy in the treatment of locally advanced cervical cancer, as well as to analyze longterm treatment outcomes.

Material and methods. A systemic literature review was conducted using medline, cochrane library, and elibrary databases in the interval time between 2003 and 2020.

Results. The review describes the mechanisms of biological efficiency of local hyperthermia and evaluates the effect of hyperthermia combined with chemotherapy and radiation therapy on cancer cells. Analysis of the thermobiological effects of local hyperthermia indicates that it is a potent sensitizer of cell killing by ionizing radiation and chemotherapy. The increase in tumor radiosensitivity is caused by the inhibition of the repair processes of damaged dna strands. Hyperthermia enhances perfusion and oxygenation of hypoxic tumor cells with a consecutive increase in tumor radiosensitivity. During chemotherapy, local hyperthermia ensures the maximum targeted delivery of cytotoxic agents to the tumor, thus increasing the effectiveness of treatment. Moreover, local hyperthermia has a direct cytotoxic effect on tumor cells. Randomized trials on the use of hyperthermia in the treatment of locally advanced cervical cancer have shown positive immediate and long-term treatment outcomes.

Conclusion. Local hyperthermia combined with chemotherapy and radiation therapy is a promising treatment modality for locally advanced cervical cancer, because it can significantly improve treatment outcomes and reduce the frequency of early and late adverse effects. However, despite the available world experience, there are no unified methodological approaches to local hyperthermia, and therefore further research is required.

1. Globocan 2018: Estimated cancer incidence, mortality and prevalence worldwide in November 2018 [Internet]. URL: http://globocan.iarc.fr (cited 05.02.2018).

2. Каприн А.Д., Старинский В.В., Петрова Г.В. Злокачественные новообразования в России в 2018 году (заболеваемость и смертность). М., 2019. 250 с. [Kaprin A.D., Starinskiy V.V., Petrova G.V. Malignant neoplasms in Russia in 2018 (morbidity and mortality). Moscow, 2019. 250 p. (in Russian)].

3. World Health Organization. Cervical Cancer – Early Diagnosis and Screening. Geneva, Switzerland, 2018.

4. Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration. Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol. 2008 Dec 10; 26(35): 5802–12. doi: 10.1200/JCO.2008.16.4368.

5. Hanna T.P., Delaney G.P., Barton M.B. The population benefit of radiotherapy for gynaecological cancer: Local control and survival estimates. Radiother Oncol. 2016 Sep; 120(3): 370–377. doi: 10.1016/j.radonc.2016.04.008.

6. Li H., Wu X., Cheng X. Advances in diagnosis and treatment of metastatic cervical cancer. J Gynecol Oncol. 2016; 27(4): e43. doi: 10.3802/jgo.2016.27.e43.

7. Lutgens L., van der Zee J., Pijls-Johannesma M., De Haas-Kock D.F., Buijsen J., Mastrigt G.A., Lammering G., De Ruysscher D.K., Lambin P. Combined use of hyperthermia and radiation therapy for treating locally advanced cervical carcinoma. Cochrane Database Syst Rev. 2010 Jan 20; (1): CD006377. doi: 10.1002/14651858.CD006377.pub2.

8. Datta N.R., Stutz E., Gomez S., Bodis S. Efficacy and Safety Evaluation of the Various Therapeutic Options in Locally Advanced Cervix Cancer: A Systematic Review and Network Meta-Analysis of Randomized Clinical Trials. Int J Radiat Oncol Biol Phys. 2019 Feb 1; 103(2): 411–437. doi: 10.1016/j.ijrobp.2018.09.037.

9. Datta N.R., Kok H.P., Crezee H., Gaipl U.S., Bodis S. Integrating Loco-Regional Hyperthermia Into the Current Oncology Practice: SWOT and TOWS Analyses. Front Oncol. 2020 Jun 12; 10: 819. doi: 10.3389/fonc.2020.00819.

10. Ihara M., Takeshita S., Okaichi K., Okumura Y., Ohnishi T. Heat exposure enhances radiosensitivity by depressing DNA-PK kinase activity during double strand break repair. Int J Hyperthermia. 2014 Mar; 30(2): 102–9. doi: 10.3109/02656736.2014.887793.

11. Datta N.R., Ordóñez S.G., Gaipl U.S., Paulides M.M., Crezee H., Gellermann J., Marder D., Puric E., Bodis S. Local hyperthermia combined with radiotherapy and-/or chemotherapy: recent advances and promises for the future. Cancer Treat Rev. 2015 Nov; 41(9): 742–53. doi: 10.1016/j.ctrv.2015.05.009.

12. Dewhirst M.W., Lee C.T., Ashcraft K.A. The future of biology in driving the field of hyperthermia. Int J Hyperthermia. 2016; 32(1): 4–13. doi: 10.3109/02656736.2015.1091093.

13. Kuo M.T. Redox regulation of multidrug resistance in cancer chemotherapy: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal. 2009 Jan; 11(1): 99–133. doi: 10.1089/ars.2008.2095.

14. Hanahan D., Weinberg R.A. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4; 144(5): 646–74. doi: 10.1016/j.cell.2011.02.013.

15. van den Tempel N., Horsman M.R., Kanaar R. Improving efficacy of hyperthermia in oncology by exploiting biological mechanisms. Int J Hyperthermia. 2016; 32(4): 446–54. doi: 10.3109/02656736.2016.1157216.

16. Weiss C., Engehausen D.G., Krause F.S., Papadopoulos T., Dunst J., Sauer R., Rödel C. Radiochemotherapy with cisplatin and 5-fluorouracil after transurethral surgery in patients with bladder cancer. Int J Radiat Oncol Biol Phys. 2007 Jul 15; 68(4): 1072–80. doi: 10.1016/j.ijrobp.2007.01.054.

17. Westermann A.M. Cisplatin combined with radiation therapy and hyperthermia in treating patients with stage II, stage III, or stage IV cervical cancer [Internet]. URL: https://clinicaltrials.gov/ct2/show/NCT00008112 (cited 05.02.2018).

18. Lutgens L.C., Koper P.C., Jobsen J.J., van der Steen-Banasik E.M., Creutzberg C.L., van den Berg H.A., Ottevanger P.B., van Rhoon G.C., van Doorn H.C., Houben R., van der Zee J. Radiation therapy combined with hyperthermia versus cisplatin for locally advanced cervical cancer: Results of the randomized RADCHOC trial. Radiother Oncol. 2016 Sep; 120(3): 378–382. doi: 10.1016/j.radonc.2016.02.010.

19. Cihoric N., Tsikkinis A., van Rhoon G., Crezee H., Aebersold D.M., Bodis S., Beck M., Nadobny J., Budach V., Wust P., Ghadjar P. Hyperthermia-related clinical trials on cancer treatment within the ClinicalTrials.gov registry. Int J Hyperthermia. 2015; 31(6): 609–14. doi: 10.3109/02656736.2015.1040471.

20. Crezee J., van Leeuwen C.M., Oei A.L., van Heerden L.E., Bel A., Stalpers L.J., Ghadjar P., Franken N.A., Kok H.P. Biological modelling of the radiation dose escalation effect of regional hyperthermia in cervical cancer. Radiat Oncol. 2016 Feb 2; 11: 14. doi: 10.1186/s13014-016-0592-z.

21. Sun X., Xing L., Ling C.C., Li G.C. The effect of mild temperature hyperthermia on tumour hypoxia and blood perfusion: relevance for radiotherapy, vascular targeting and imaging. Int J Hyperthermia. 2010; 26(3): 224–31. doi: 10.3109/02656730903479855.

22. Kislichko A.G., Kislichko S.A., Pozdeyev N.M. Treatment effectiveness hyperthermia in combination treatment in non-small cell cancer of the lung (review). Medical Newsletter of Vyatka. 2012, 1: 54–9. (in Russian).

23. Sharma S., Singhal S., Sandhu A.P., Ghoshal S., Gupta B.D., Yadav N.S. Local thermo-radiotherapy in carcinoma cervix: improved local control versus increased incidence of distant metastasis. Asia Oceania J Obstet Gynaecol. 1991 Mar; 17(1): 5–12. doi: 10.1111/j.1447-0756.1991.tb00244.x.

24. Datta N.R., Bose A.K., Kapoor H.K. Thermoradiotherapy in the management of carcinoma cervix (stage IIIB): a controlled clinical study. Indian Med Gazette 1987; 121: 68–71.

25. Chen H., Jun-Jie F., Wei L. A randomized trial of hyperthermoradiochemotherapy for uterine cervix cancer. Chin J Clin Oncol 1997; 24: 249–251.

26. Harima Y., Nagata K., Harima K., Ostapenko V.V., Tanaka Y., Sawada S. A randomized clinical trial of radiation therapy versus thermoradiotherapy in stage IIIB cervical carcinoma. Int J Hyperthermia. 2001 Mar-Apr; 17(2): 97–105. doi: 10.1080/02656730010001333.

27. van der Zee J., González González D., van Rhoon G.C., van Dijk J.D., van Putten W.L., Hart A.A. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Dutch Deep Hyperthermia Group. Lancet. 2000 Apr 1; 355(9210): 1119–25. doi: 10.1016/s0140-6736(00)02059-6.

28. van der Zee J., González G.D. The Dutch Deep Hyperthermia Trial: results in cervical cancer. Int J Hyperthermia. 2002 Jan-Feb; 18(1): 1–12. doi: 10.1080/02656730110091919.

29. Franckena M., Stalpers L.J., Koper P.C., Wiggenraad R.G., Hoogenraad W.J., van Dijk J.D., Wárlám-Rodenhuis C.C., Jobsen J.J., van Rhoon G.C., van der Zee J. Long-term improvement in treatment outcome after radiotherapy and hyperthermia in locoregionally advanced cervix cancer: an update of the Dutch Deep Hyperthermia Trial. Int J Radiat Oncol Biol Phys. 2008 Mar 15; 70(4): 1176–82. doi: 10.1016/j.ijrobp.2007.07.2348.

30. van der Zee J., van Rhoon G.C. Cervical cancer: radiotherapy and hyperthermia. Int J Hyperthermia. 2006; 22(3): 229–34. doi: 10.1080/02656730600722578.

31. Vasanthan A., Mitsumori M., Park J.H., Zhi-Fan Z., Yu-Bin Z., Oliynychenko P., Tatsuzaki H., Tanaka Y., Hiraoka M. Regional hyperthermia combined with radiotherapy for uterine cervical cancers: a multi-institutional prospective randomized trial of the international atomic energy agency. Int J Radiat Oncol Biol Phys. 2005 Jan 1; 61(1): 145–53. doi: 10.1016/j.ijrobp.2004.04.057.

32. Zolciak-Siwinska A., Piotrkowicz N., Jonska-Gmyrek J., NickePsikuta M., Michalski W., Kawczyńska M., Bijok M., Bujko K. HDR brachytherapy combined with interstitial hyperthermia in locally advanced cervical cancer patients initially treated with concomitant radiochemotherapy – a phase III study. Radiother Oncol. 2013; 109(2): 194–9. doi: 10.1016/j.radonc.2013.04.011.

33. Westermann A., Mella O., Van Der Zee J., Jones E.L., Van Der SteenBanasik E., Koper P., Uitterhoeve A.L., De Wit R., Van Der Velden J., Burger C., Schem B.C., Van Der Wilt C., Dahl O., Prosnitz L.R., Van Tinteren H. Long-term survival data of triple modality treatment of stage IIB–III–IVA cervical cancer with the combination of radiotherapy, chemotherapy and hyperthermia – an update. Int J Hyperthermia. 2012; 28(6): 549–53. doi: 10.3109/02656736.2012.673047.

34. Yan X., Liu W., Yan Z. Efficacy and safety radio-chemotherapy combined with thermotherapy for cervical cancer: a meta-analysis. Chin J Evid-based Med. 2014; 14: 752–58.

35. Harima Y., Ohguri T., Imada H., Sakurai H., Ohno T., Hiraki Y., Tuji K., Tanaka M., Terashima H. A multicentre randomised clinical trial of chemoradiotherapy plus hyperthermia versus chemoradiotherapy alone in patients with locally advanced cervical cancer. Int J Hyperthermia. 2016 Nov; 32(7): 801–8. doi: 10.1080/02656736.2016.1213430.

36. Minnaar C.A., Kotzen J.A., Ayeni O.A., Naidoo T., Tunmer M., Sharma V., Vangu M.D., Baeyens A. The effect of modulated electro-hyperthermia on local disease control in HIV-positive and -negative cervical cancer women in South Africa: Early results from a phase III randomized controlled trial. PLoS One. 2019 Jun 19; 14(6): e0217894. doi: 10.1371/journal.pone.0217894.

37. Wang Y., Hong W., Che S., Zhang Y., Meng D., Shi F., Su J., Yang Y., Ma H., Liu R., Gao Y., Wang J., Hui B., Wang J., Lu J., Wang T., Liu Z., Chen H. Outcomes for Hyperthermia Combined with Concurrent Radiochemotherapy for Patients with Cervical Cancer. Int J Radiat Oncol Biol Phys. 2020 Jul 1; 107(3): 499–511. doi: 10.1016/j.ijrobp.2020.03.006.

38. Ohguri T., Harima Y., Imada H., Sakurai H., Ohno T., Hiraki Y., Tuji K., Tanaka M., Terashima H. Relationships between thermal dose parameters and the efficacy of definitive chemoradiotherapy plus regional hyperthermia in the treatment of locally advanced cervical cancer: data from a multicentre randomised clinical trial. Int J Hyperthermia. 2018 Jun; 34(4): 461–468. doi: 10.1080/02656736.2017.1352105.