Carbon ion radiotherapy: impact of tumor differentiation on local control in experimental prostate carcinomas

To summarize the research activities of the “clinical research group heavy ion therapy”, funded by the German Research Foundation (DFG, KFO 214), on the impact of intrinsic tumor characteristics (grading, hypoxia) on local tumor control after carbon ( 12 C-) ion- and photon irradiations. Three sublines of syngeneic rat prostate tumors (R3327) with various differentiation levels (highly (-H), moderately (-HI) or anaplastic (-AT1), (diameter 10 mm) were irradiated with 1, 2 and 6 fractions of either 12 C-ions or 6 MV photons using increasing dose levels. Primary endpoint was local tumor control at 300 days. The relative biological effectiveness (RBE) of 12 C-ions was calculated from TCD 50 -values (dose at 50% tumor control probability) of photons and 12 C-ions and correlated with intrinsic tumor parameters. For the HI-subline, larger tumors (diameter 18 mm) were irradiated with either carbon ions, oxygen ions or photons under ambient as well as hypoxic conditions to determine the variability of the RBE under different oxygenation levels. In addition, imaging, histology and molecular analyses were performed to decipher the underlying mechanisms. Experimental results revealed (i) a smaller variation of the TCD 50 -values between the three tumor sublines for 12 C-ions (23.6 - 32.9 Gy) than for photons (38.2 - 75.7 Gy), (ii) steeper dose-response curves for 12 C-ions, and (iii) an RBE that increased with tumor grading (1.62 ± 0.11 (H) vs 2.08 ± 0.13 (HI) vs 2.30 ± 0.08 (AT1)). Large HI-tumors resulted in a marked increase of TCD 50 , which was increased further by 15% under hypoxic relative to oxic conditions. Noninvasive imaging, histology and molecular analyses identified hypoxia as an important radioresistance factor in photon therapy. The dose-response studies revealed a higher efficacy of 12 C-ions relative to photon therapy in the investigated syngeneic tumor model. Hypoxia turned out to be at least one important radioresistance factor, which can be partly overridden by high-LET ion beams. This might be used to increase treatment effectiveness also in patients. The results of this project served as a starting point for several ongoing research projects.