Extension of the biological effective dose to the MIRD schema and possible implications in radionuclide therapy dosimetry

Abstract

In dosimetry-based treatment planning protocols, patients with rapid clearance of the radiopharmaceutical require a larger amount of initial activity than those with slow clearance to match the absorbed dose to the critical organ. As a result, the dose-rate to the critical organ is higher in patients with rapid clearance and may cause unexpected toxicity compared to patients with slow clearance. In order to account for the biological impact of different dose-rates, radiobiological modeling is beginning to be applied to the analysis of radionuclide therapy patient data. To date, the formalism used for these analyses is based on kinetics derived from activity in a single organ, the target. This does not include the influence of other source organs to the dose and dose-rate to the target organ. As a result, only self-dose irradiation in the target organ contributes to the dose-rate. In this work, the biological effective dose (BED) formalism has been extended to include the effect of multiple source organ contributions to the net dose-rate in a target organ. The generalized BED derivation has been based on the Medical Internal Radionuclide Dose Committee (MIRD) schema assuming multiple source organs following exponential effective clearance of the radionuclide. A BED-based approach to determine the largest safe dose to critical organs has also been developed. The extended BED formalism is applied to red marrow dosimetry, as well as kidney dosimetry considering the cortex and the medulla separately, since both those organs are commonly dose limiting in radionuclide therapy. The analysis shows that because the red marrow is an early responding tissue (high α/β), it is less susceptible to unexpected toxicity arising from rapid clearance of high levels of administered activity in the marrow or in the remainder of the body. In kidney dosimetry, the study demonstrates a complex interplay between clearance of activity in the cortex and the medulla, as well as the initial activity ratio and the S value ratio between the two. In some a) sebastien.baechler@chuv.ch. scenarios, projected BED based on both the cortex and the medulla is a more appropriate constraint on the administered activity than the BED based on the cortex only. Furthermore, different fractionated regimens were considered to reduce renal toxicity. The MIRD-based BED formalism is expected to be useful for patient-specific adjustments of activity and to facilitate the investigation of dose-toxicity correlations with respect to dose-rate and tissue repair mechanism. NIH Public Access

MIRD Pamphlet No. 20: The Effect of Model Assumptions on Kidney Dosimetry and Response—Implications for Radionuclide Therapy

“…This equivalence is strictly true only for the self-dose terms. If the target organ is being irradiated by other organ or suborgan components from radionuclides with high photon fluences, then the derivation should account for the impact of cross dose on the target organ dose rate (55).…”

Chemoradionuclide Therapy with186Re-Labeled Liposomal Doxorubicin: Toxicity, Dosimetry, and Therapeutic Response

“…It is becoming increasingly clear that dose-rate considerations should be taken into account during radionuclide dosimetry. 66,67 Biological effective dose relates absorbed dose and dose rate with radiosensitivity and radiation damage repair using the linear quadratic model and could be investigated in the future as a method for comparing the differences in doseresponse and dose-toxicity between 186 Re-Doxil and 186 Re-PEG-liposomes, as they would have different dose rates because of their significantly different circulation time.…”

Biologically effective dose in fractionated molecular radiotherapy—application to treatment of neuroblastoma with131I-mIBG

“…For this purpose an expression for the Lea-Catcheside Gfactor is derived, which in contrast to the previously used expression (Cremonesi et al, 2006;Baechler et al, 2008;Cremonesi et al, 2008), includes the possibility that pairs of sublethal damage caused by radiation associated with different administrations combine into a lethal damage. As shown by (7) the function ,∞ in the Lea-Catcheside G-factor integrated up to infinite time for n administrations, depends on λ, µ, n and t, while the formerly used equation (6), depends on the same parameters except for t.…”

“…For situations when the absorbed-dose rate curve has the same monoexponential behaviour in all administrations, previous publications (Cremonesi et al, 2006;Baechler et al, 2008;Cremonesi et al, 2008) have given the following expression for BED:…”

“…For fractionated MRT, i.e. MRT given in several administrations of activity, it has also been assumed that the BED is linearly additive (Cremonesi et al, 2006;Baechler et al, 2008;Cremonesi et al, 2008). However, this assumption is not valid when administrations are performed close in time, so that there is an appreciable interplay between the absorbed-dose rate curves corresponding to different administrations, i.e.…”