Presentation Response of hypoxic tumors – do we take advantage from high-LET?

古澤, 佳也

The oxygen effect is the biggest modification factor in radiobiological effects. A three times higher dose of photons is required to obtain the same biological effect, such as cell killing, under anoxic (0 % pO2) condition than under oxic condition. It is commonly believed that OER values will be reduced with increasing LET. However, the OER value is still large even for high-LET heavy-ion beams, e.g. ~2 at 100 keV/µm. Oxygen concentration in hypoxic tumor tissue is around ~0.5 % pO2, and the OER value is ~1.5 to 100 keV/µm beam. This hypoxic condition may cause the recurrence of tumor after radiotherapy. A dependence of OER values to pO2 is well known for photons. However LET dependence of the OER is only known for 0 % anoxic condition. To most efficiently kill the tumor in heavy ion radiotherapy, we have to know the OER values at different LETs and at different pO2 values to estimate therapeutic outcome for heavy ion radiotherapy. Painting methods (Dose-, LET-, and/or Kill-painting) are proposed to overcome the hypoxia with ion beam radiotherapy. Therefore, we have measured and published 3D-functional OER values as function of LETs and pO2s[1]. In addition, we measured the radiobiological depths-cell-kill distribution of cells in different pO2 (0, 0.5 and 21 %) using a special simulating irradiation chamber with a 3D-OER distribution. Oxygen effect is not yet taken into account in radiotherapy, because it is difficult to measure the distribution of oxygen concentration within tumors in individual patients. However the measurement of oxygen in tumors of individuals is now improving with development of PET probes (18F-FMISO, 18F-FAZA, Cu-ATSMs and so on). The oxygen effect has been neglected in HIMAC carbon therapy from the start of clinical trial in 1994 until now. Multi-institutional clinical research with 62Cu-ATSM is currently being performed in Japan. An open-PET, which can be installed in the therapeutic beam line is in development at NIRS. There is a big possibility to observe oxygen concentration in real time in the near future, where quick change of the treatment plan with automated TPS following the change of oxic area may lead to better outcome. However, acute hypoxia (or local oxygen change; LOC) is still a big concern. Relative clinical effectiveness of carbon ion at different OER values and LETs was reanalyzed with RCR model in silico. It is suggested that hypoxic tumors could be controlled to almost the same degree as well-oxygenated tumors, if LOCs status was allowed to influence the treatment plan between the fractions[2]. With regard to tumor control, extreme hypofractionation should thus be avoided in order to allow for interfraction LOCs. [1] Tinganelli, et al., Scientific Reports 5; 17016 (2015) [2] Antonovic, et al., Journal of Radiation Research 55; 902-11 (2014)
2nd Heidelberg Symposium on Novel Techniques in Ion Beam Radiotherapy

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