1. Journal Club Dept. Of Medical Physics Faculty of Medicine Iran Uni. Of Medical Sciences Hyperthermia SR Mahdavi 1395/07/27

2. Article: Overview Hyperthermia: a Potent Enhancer of Radiotherapy Clinical Oncology (2007) 19: 418 - 426 M. R. Horsman, J. Overgaard Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark

3. Importance of Hyperthermia topic Extensive preclinical data showing that hyperthermia (HT) combination with radiation is one of the most effective radiation sensitizers. Selection Criteria: 1. HT as a complementary medicine, 2. Established technique in developed countries 3. Wide research area; HT+RT/Ch.T 4. A branch of Clinical application of Medical Physics 5. Research design in the physics of HT (QA, thermometry,…..) 6. This facility is now present in Iran

4. Search strategy  This article was an internet research product in the field of HT Explain.  I know Prof. Michael Horsman well. He is PhD in radiation biology in Department of Clinical Medicine - Department of Experimental Clinical Oncology, Aarhus University Hospital.

5. Research methodology: Purpose  Authors try to say that: 1. Although hyperthermia per se is probably only useful in palliative situations and has no role to play in the curative treatment of human tumours. But; 2. There is definitive evidence that when hyperthermia is combined with other treatments, such as Radiation, significant improvements in clinical outcome are possible..  In fact hyperthermia is probably one of the most effective radiation sensitizers known.

6. Research methodology (cont’d): Combining Heat and Radiation in vitro and in vivo Interaction between heat and radiation is dependent on a number of factors. These include heating temperature, heating time, and sequence and time interval between the two modalities, as illustrated in Fig. 1.

8. Combination of heat and radiation in vitro The exact mechanism by which heat sensitizes cells to radiation is not known, but most evidence suggests that heat primarily interferes with the cells’ ability to deal with radiation-induced DNA damage

9. Combination of heat and radiation in vivo In vivo; the heat-induced enhancement of radiation damage generally result of two mechanisms: 1. Direct radio-sensitization as in vitro 2. Indirect mechanism (HT toxicity): heat kills the radio-resistant hypoxic cell population. Tumour’s vascular supply is structurally and functionally abnormal.

10. This results in the development of areas that are nutrient deprived, low in oxygen, and highly acidic. Cells under hypoxic conditions are more sensitive to the lethal effects of hyperthermia than cells in a well-oxygenated environment. Combination of heat and radiation in vivo

11. Factors Influencing the Response to Single Treatments 1. Generally, for tumours the thermal enhancement ratio (TER) of the radiation response is greatest when the radiation and heat are administered simultaneously (Fig. 2). 2. The larger TER pre-radiation heating is may be indicative of a persistent thermosensitization (direct) mechanism. 3. Post-radiation heating enhancement can be due to HT radio-resistant cell killing (indirect) effect.

13. Findings  For simultaneous treatment no therapeutic advantage is to be expected.  Sequential treatment has little or no effect in normal tissues means that there is a substantial therapeutic benefit with it.  Thermotolerance: Depends on the cell type, temperature, duration, and the interval between successive heat treatments.

14. Tissue temperature fluctuation: Step-down heating (SDH) and SUH. With SUH the tumour response is the result of an additive effect of the two heat treatments, whereas with SDH not only is there additional cell killing from the higher temperature, but significant sensitization to the second heat treatment is also observed. Findings

15. Other findings discussed in this paper Role of the Tumour Vasculature Tumour micro-environmental changes Effect of heat on the tumour vasculature

16. Findings, cont’d: Clinical Trials with Heat and Radiation Results show loco-regional control, which is the most relevant end point for locally applied treatments, and show significant heatinduced improvements in a number of distinct sites, including chest wall, cervix, rectum, bladder, melanoma, and head and neck.

17. Table 1. Meta analysis of all clinical trials in which patients were randomised to receive radiation alone or radiation with hyperthermia*

18. Critical appraisal  Type of heat generating method  Radiofrequency and Capacitive HT  Difficulties in adequately and effectively heating tumours in patients (Physics and technical issues)  These types of studies can have important role in improvement of HT methodology and clinical application.

19. Conclusion  So, how can we change the current thinking about the application of hyperthermia and radiation? Clearly, with so many randomised trials showing obvious benefits it is unlikely that carrying out additional trials would be the answer. What is needed are improvements in the physics and biology so that preferential tumour heating becomes easier.

20. Group discussion  Opening clinical trials with emphasis on physics and biology  Treatment planning  Phantom design for thermal mapping and measurement

21. بسیار متشکرم

24. Methods to increase tumour temperature