Original Article
Lethal and nonlethal chromosome aberrations by gamma rays and heavy ions: a cytogenetic perspective on dose fractionation in hadron radiotherapy
Abstract
Background: With ions heavier than protons now being used in radiotherapy, consideration has been given to the use of fewer dose fractions. Because it is among the best surrogate measures of cell killing and carcinogenic potential, damage to chromosomes relates to the clinical objectives of minimizing normal tissue damage, and lessening the chance of treatment-related second cancers. Curvature in acute dose response relationships plays an important role in radiotherapy, since it implies that a dose-fractionation effect will be observed.
Methods: Human lymphocytes, irradiated with either 662 keV 137Cs gamma rays or 1 GeV/amu 56Fe ions, were assessed for chromosome aberrations at their first postirradiation mitosis by mFISH.
Results: As measured by the frequency of metaphases not containing lethal aberrations, the survival curve for iron ions was exponential, whereas that for gamma rays was decidedly curvilinear. We observed an apparent slight curvature in the dose response for total chromosome exchange breakpoints following exposure to 56Fe ions, but a curvilinear model did not receive overwhelming statistical support. More importantly, support for the curvilinear model decreased when only cells containing transmissible (nonlethal) aberrations were considered. This is in stark contrast to the results for low LET 137Cs photons, where curvilinearity in the dose response had overwhelming support irrespective of whether total or only nonlethal aberrations were considered.
Conclusions: We make the assumption that high atomic number, high-energy (HZE) iron ions mimic the biological effects of the high-dose/high-LET (Bragg-peak) region of ions used in hadron therapy. To the extent this is true our results suggest that fractionation would not change the biological response for cell killing within the target volume. We further assume that the biological effects of gamma photons are principally equivalent to those of the low-dose/low-LET entrance (plateau) region of the dE/dx profile. In that case, fractionation is expected to elicit considerable sparing for the low-LET/low-dose entrance region occupied by normal tissues. Consequently, while hypo-fractionation would provide no additional benefit insofar as tumor cell killing is concerned, it may well increase the risk of normal tissue damage. Since most secondary solid tumors are thought to be formed near the treatment margin of the high-LET/highdose region, neither will fractionation have an effect on the induction of cells containing only nonlethal aberrations. Consequently, the incidence of second cancers is unlikely to be unaffected by any type of fractionation schedule. Thus, from a purely cytogenetic perspective, we conclude that hypo-fractionated hadron radiotherapy is a precarious proposition to be considered with due caution.
Methods: Human lymphocytes, irradiated with either 662 keV 137Cs gamma rays or 1 GeV/amu 56Fe ions, were assessed for chromosome aberrations at their first postirradiation mitosis by mFISH.
Results: As measured by the frequency of metaphases not containing lethal aberrations, the survival curve for iron ions was exponential, whereas that for gamma rays was decidedly curvilinear. We observed an apparent slight curvature in the dose response for total chromosome exchange breakpoints following exposure to 56Fe ions, but a curvilinear model did not receive overwhelming statistical support. More importantly, support for the curvilinear model decreased when only cells containing transmissible (nonlethal) aberrations were considered. This is in stark contrast to the results for low LET 137Cs photons, where curvilinearity in the dose response had overwhelming support irrespective of whether total or only nonlethal aberrations were considered.
Conclusions: We make the assumption that high atomic number, high-energy (HZE) iron ions mimic the biological effects of the high-dose/high-LET (Bragg-peak) region of ions used in hadron therapy. To the extent this is true our results suggest that fractionation would not change the biological response for cell killing within the target volume. We further assume that the biological effects of gamma photons are principally equivalent to those of the low-dose/low-LET entrance (plateau) region of the dE/dx profile. In that case, fractionation is expected to elicit considerable sparing for the low-LET/low-dose entrance region occupied by normal tissues. Consequently, while hypo-fractionation would provide no additional benefit insofar as tumor cell killing is concerned, it may well increase the risk of normal tissue damage. Since most secondary solid tumors are thought to be formed near the treatment margin of the high-LET/highdose region, neither will fractionation have an effect on the induction of cells containing only nonlethal aberrations. Consequently, the incidence of second cancers is unlikely to be unaffected by any type of fractionation schedule. Thus, from a purely cytogenetic perspective, we conclude that hypo-fractionated hadron radiotherapy is a precarious proposition to be considered with due caution.
