Optimization of total body irradiation: the match between (maximal) leukemic cell kill and (minimal) late effects

Abstract

Optimization of total body irradiation: the match between (maximal) leukemic cell kill and (minimal) late effects: In this thesis, cataract formation and renal dysfunction as late effects of high-dose total body irradiation (TBI) as part of the conditioning before hematological stem cell transplantation (HSCT), are considered in more detail. Discussed are factors influencing their appearance. In case of cataract formation, the final severity of the lesion and resulting complaints are described. Also possibilities to prevent severe cataracts, late renal dysfunction and late effects of high-dose TBI for HSCT in general are investigated or discussed. With respect to cataract formation, the values of the tissue specific parameter, alpha/beta, and the rate of repair of sublethal damage, mu, for lens tissue are derived. They were unknown yet and are required to calculate the cataract incidence for a specific TBI regimen, using the linear-quadratic (LQ) concept to normalize the TBI regimens into biologic effective doses (BEDs). Furthermore, to find the requirements for an optimal TBI regimen with maximal leukemic cell kill and minimal late effects, a study was performed comparing the results of various TBI regimens obtained from a literature search. Finally, the results of HSCT/TBI in the Netherlands are discussed, with special attention for the effectiveness of the various TBI regimens as part of the conditioning for HSCT, while also the effects of other variables, such as patient age, gender and type of transplantation, are investigated. Conclusions are: After single-dose or two-fractions TBI, a cataract will develop in 100% of the patients. Only about 45% of those patients experience severe visual impairment (SVI), requiring cataract surgery. Steroids shorten the latency time of a cataract and adversely influence the severity. In children, eye shielding during TBI reduced the incidence of SVI to 3% and did not increase the risk for relapse. An alpha/beta of 0.75 Gy and a mu of 0.65 h-1 were found. Unexpectedly, late renal dysfunction after TBI was found to be a risk of almost all TBI regimens, even when multifractionated. Shielding of the kidneys therefore seems unavoidable. As leukemic cells are also present in the shadow of shielding blocks and the measure of shielding can be considerably lower in multifractionated TBI, fractionation of the TBI should be preferred. From analysis of literature-derived data we found that the BED for leukemic cells of an optimal TBI regimen is as high as possible: > 15 Gy, while BEDs for lung kidney and eye lens tissue are not exceeding 15, 17 and 45 Gy, respectively. In The Netherlands, using one- or two-fraction TBI, a regimen with a high BED does not result in a better survival than a regimen with a relatively low BED. Only the non-relapse mortality (NRM) and the relapse incidence (RI) differ. Age appeared to be of significant influence on survival and NRM in favor of younger patients, there was no influence on RI. Gender was also of significant influence on survival and NRM, in favor of male patients; transplantation type (autologous or allogeneic HSCT) was not of influence on survival.