Cellular Response to Exponentially Increasing and Decreasing Dose Rates: Implications for Treatment Planning in Targeted Radionuclide Therapy

Abstract

The treatment of cancer using targeted radionuclide therapy is of interest to nuclear medicine and radiation oncology because of its potential for killing tumor cells while minimizing dose-limiting toxicities to normal tissue. The ionizing radiations emitted by radiopharmaceuticals deliver radiation absorbed doses over protracted periods of time with continuously varying dose rates. As targeted radionuclide therapy becomes a more prominent part of cancer therapy, accurate models for estimating the biologically effective dose (BED) or equieffective dose (EQD2α/β) will become essential for treatment planning. This study examines the radiobiological impact of the dose rate increase half-time during the uptake phase of the radiopharmaceutical. MDA-MB-231 human breast cancer cells and V79 Chinese hamster lung fibroblasts were irradiated chronically with 662 keV γ rays delivered with time-varying dose rates that are clinically relevant. The temporal dose-rate patterns were: 1. acute, 2. exponential decrease with a half-time of 64 h (Td = 64 h), 3. initial exponential increase to a maximum (half time Ti = 2, 8 or 24 h) followed by exponential decrease (Td = 64 h). Cell survival assays were conducted and surviving fractions were determined. There was a marked reduction in biological effect when Ti was increased. Cell survival data were tested against existing dose-response models to assess their capacity to predict response. Currently accepted models that are used in radiation oncology overestimated BED and EQD2α/β at low-dose rates and underestimated them at high-dose rates. This appears to be caused by an adaptive response arising as a consequence of the initial low-dose-rate phase of exposure. An adaptive response function was derived that yields more accurate BED and EQD2α/β values over the spectrum of dose rates and absorbed doses delivered. Our experimental data demonstrate a marked increase in cell survival when the dose-rate-increase half-time is increased, thereby suggesting an adaptive response arising as a consequence of this phase of exposure. We have modified conventional radiobiological models used in the clinic for brachytherapy and external beams of radiation to account for this phenomenon and facilitate their use for treatment planning in targeted radionuclide therapy.

Radiosensitivity of colorectal cancer to 90Y and the radiobiological implications for radioembolisation therapy

“…Furthermore, the protraction of dose delivery for 90 Y SIRT adds another level of complexity. This effect is encapsulated by the Lea–Catcheside model of sublethal-damage repair (Dale 2018) and has previously been used to describe the in vitro cellular response to protracted photon exposure (Solanki et al 2017). However, studies using 90 Y are needed to answer fundamental questions regarding differences in the radiobiological response to 90 Y β − -particles and photons of clinically relevant energy.…”

ICRU REPORT 96, Dosimetry-Guided Radiopharmaceutical Therapy

“…The relevance of this to RPT is illustrated in Fig. 4.10 (Solanki et al , 2017). In this experimental study, the dose rate profiles were varied by changing the extrapolated initial dose rate ( r o ), dose rate increase half-time ( T i ), and dose rate decrease half-time ( T d ) using a custom 137 Cs irradiator fitted with a continuously adjustable mercury attenuator (Howell et al , 1994b; 1998b).…”

“…Some survival curves may not follow this pattern. Furthermore, complex absorbed dose rate patterns can also affect the shape of the survival curve (Solanki et al, 2017). In these instances, sRBEX may have some dependence on absorbed dose; however, any remaining variabilities would reflect fundamental biological behavior.…”

“…Equation (4.11) is the most recognized form for BED in nuclear medicine, but it is only valid for organs or ROIs whose time-dependent absorbed dose rate is described by a monoexponential function. More complex forms of the BED have been derived for the multicomponent exponential absorbed dose rate curves that are typically observed in nuclear medicine (Howell et al , 1994b; Solanki et al , 2017). A formulation applicable to the MIRD S-coefficient methodology has also been reported (Baechler et al , 2008).…”

Radiation repair models for clinical application

“…exposure, but the same modelling principles can be applied to pulsed brachytherapy, 25,26,35 permanent implants, 32,33,36,37 and biologically targeted radiotherapy. [38][39][40][41] Some summary points are: (a) The fractional amount of SLD repair occurring in successive time intervals is not always constant-the repair taking place in successive time intervals may reduce with increasing time after irradiation, particularly in some normal tissues. This is conventionally explained by assuming that there are two or more exponential components of repair.…”