Generalized methods for predicting biological response to mixed radiation types and calculating equieffective doses (EQDX).

BACKGROUND: Predicting biological responses to mixed radiation types is of considerable importance when combining radiation therapies that use multiple radiation types and delivery regimens. These may include the use of both low- and high-linear energy transfer (LET) radiations. A number of theoretical models have been developed to address this issue. However, model predictions do not consistently match published experimental data for mixed radiation exposures. Furthermore, the models are often computationally intensive. Accordingly, there is a need for efficient analytical models that can predict responses to mixtures of low- and high-LET radiations. Additionally, a general formalism to calculate equieffective dose (EQDX) for mixed radiations is needed. PURPOSE: To develop a computationally efficient analytical model that can predict responses to complex mixtures of low- and high-LET radiations as a function of either absorbed dose or EQDX. METHODS: The Zaider-Rossi model (ZRM) was modified by replacing the geometric mean of the quadratic coefficients in the interaction term with the arithmetic mean. This modified ZRM model (mZRM) was then further generalized to any number of radiation types and its validity was tested against published experimental observations. Comparisons between the predictions of the ZRM and mZRM, and other models, were made using two and three radiation types. In addition, a generalized formalism for calculating EQDX for mixed radiations was developed within the context of mZRM and validated with published experimental results. RESULTS: The predictions of biological responses to mixed-LET radiations calculated with the mZRM are in better agreement with experimental observations than ZRM, especially when high- and low-LET radiations are mixed. In these situations, the ZRM overestimated the surviving fraction. Furthermore, the EQDX calculated with mZRM are in better agreement with experimental observations. CONCLUSION: The mZRM is a computationally efficient model that can be used to predict biological response to mixed radiations that have low- and high-LET characteristics. Importantly, interaction terms are retained in the calculation of EQDX for mixed radiation exposures within the mZRM framework. The mZRM has application in a wide range of radiation therapies, including radiopharmaceutical therapy.

Marshalling the Potential of Auger Electron Radiopharmaceutical Therapy.

Auger electron (AE) radiopharmaceutical therapy (RPT) may have the same therapeutic efficacy as α-particles for oncologic small disease, with lower risks of normal-tissue toxicity. The seeds of using AE emitters for RPT were planted several decades ago. Much knowledge has been gathered about the potency of the biologic effects caused by the intense shower of these low-energy AEs. Given their short range, AEs deposit much of their energy in the immediate vicinity of their site of decay. However, the promise of AE RPT has not yet been realized, with few agents evaluated in clinical trials and none becoming part of routine treatment so far. Instigated by the 2022 "Technical Meeting on Auger Electron Emitters for Radiopharmaceutical Developments" at the International Atomic Energy Agency, this review presents the current status of AE RPT based on the discussions by experts in the field. A scoring system was applied to illustrate hurdles in the development of AE RPT, and we present a selected list of well-studied and emerging AE-emitting radionuclides. Based on the number of AEs and other emissions, physical half-life, radionuclide production, radiochemical approaches, dosimetry, and vector availability, recommendations are put forward to enhance and impact future efforts in AE RPT research.

Efficacy of HER2-Targeted Intraperitoneal 225Ac α-Pretargeted Radioimmunotherapy for Small-Volume Ovarian Peritoneal Carcinomatosis.

Epithelial ovarian cancer (EOC) is often asymptomatic and presents clinically in an advanced stage as widespread peritoneal microscopic disease that is generally considered to be surgically incurable. Targeted α-therapy with the α-particle-emitting radionuclide 225Ac (half-life, 9.92 d) is a high-linear-energy-transfer treatment approach effective for small-volume disease and even single cells. Here, we report the use of human epidermal growth factor receptor 2 (HER2) 225Ac-pretargeted radioimmunotherapy (PRIT) to treat a mouse model of human EOC SKOV3 xenografts growing as peritoneal carcinomatosis (PC). Methods: On day 0, 105 SKOV3 cells transduced with a luciferase reporter gene were implanted intraperitoneally in nude mice, and tumor engraftment was verified by bioluminescent imaging (BLI). On day 15, treatment was started using 1 or 2 cycles of 3-step anti-HER2 225Ac-PRIT (37 kBq/cycle as 225Ac-Proteus DOTA), separated by a 1-wk interval. Efficacy and toxicity were monitored for up to 154 d. Results: Untreated PC-tumor-bearing nude mice showed a median survival of 112 d. We used 2 independent measures of response to evaluate the efficacy of 225Ac-PRIT. First, a greater proportion of the treated mice (9/10 1-cycle and 8/10 2-cycle; total, 17/20; 85%) survived long-term compared with controls (9/27, 33%), and significantly prolonged survival was documented (log-rank [Mantel-Cox] P = 0.0042). Second, using BLI, a significant difference in the integrated BLI signal area to 98 d was noted between controls and treated groups (P = 0.0354). Of a total of 8 mice from the 2-cycle treatment group (74 kBq total) that were evaluated by necropsy, kidney radiotoxicity was mild and did not manifest itself clinically (normal serum blood urea nitrogen and creatinine). Dosimetry estimates (relative biological effectiveness-weighted dose, where relative biological effectiveness = 5) per 37 kBq administered for tumors and kidneys were 56.9 and 16.1 Gy, respectively. One-cycle and 2-cycle treatments were equally effective. With immunohistology, mild tubular changes attributable to α-toxicity were observed in both therapeutic groups. Conclusion: Treatment of EOC PC-tumor-bearing mice with anti-HER2 225Ac-PRIT resulted in histologic cures and prolonged survival with minimal toxicity. Targeted α-therapy using the anti-HER2 225Ac-PRIT system is a potential treatment for otherwise incurable EOC.

Advancements in the use of Auger electrons in science and medicine during the period 2015-2019.

Auger electrons can be highly radiotoxic when they are used to irradiate specific molecular sites. This has spurred basic science investigations of their radiobiological effects and clinical investigations of their potential for therapy. Focused symposia on the biophysical aspects of Auger processes have been held quadrennially. This 9th International Symposium on Physical, Molecular, Cellular, and Medical Aspects of Auger Processes at Oxford University brought together scientists from many different fields to review past findings, discuss the latest studies, and plot the future work to be done. This review article examines the research in this field that was published during the years 2015-2019 which corresponds to the period since the last meeting in Japan. In addition, this article points to future work yet to be done. There have been a plethora of advancements in our understanding of Auger processes. These advancements range from basic atomic and molecular physics to new ways to implement Auger electron emitters in radiopharmaceutical therapy. The highly localized doses of radiation that are deposited within a 10 nm of the decay site make them precision tools for discovery across the physical, chemical, biological, and medical sciences.

Predicting response of micrometastases with MIRDcell V3: proof of principle with 225Ac-DOTA encapsulating liposomes that produce different activity distributions in tumor spheroids.

PURPOSE: The spatial distribution of radiopharmaceuticals within multicellular clusters is known to have a significant effect on their biological response. Most therapeutic radiopharmaceuticals distribute nonuniformly in tissues which makes predicting responses of micrometastases challenging. The work presented here analyzes published temporally dependent nonuniform activity distributions within tumor spheroids treated with actinium-225-DOTA encapsulating liposomes (225Ac-liposomes) and uses these data in MIRDcell V3.11 to calculate absorbed dose distributions and predict biological response. The predicted responses are compared with experimental responses. METHODS: Four types of liposomes were prepared having membranes with different combinations of release (R) and adhesion (A) properties. The combinations were R-A-, R-A+, R+A-, and R+A+. These afford different penetrating properties into tissue. The liposomes were loaded with either carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) or 225Ac. MDA-MB-231 spheroids were treated with the CFDA-SE-liposomes, harvested at different times, and the time-integrated CFDA-SE concentration at each radial position within the spheroid was determined. This was translated into mean 225Ac decays/cell versus radial position, uploaded to MIRDcell, and the surviving fraction of cells in spherical multicellular clusters was simulated. The MIRDcell-predicted surviving fractions were compared with experimental fractional-outgrowths of the spheroids following treatment with 225Ac-liposomes. RESULTS: The biological responses of the multicellular clusters treated with 225Ac-liposomes with physicochemical properties R+A+, R-A+, and R-A- were predicted by MIRDcell with statistically significant accuracy. The prediction for R+A- was not predicted accurately. CONCLUSION: In most instances, MIRDcell predicts responses of spheroids treated with 225Ac-liposomes that result in different tissue-penetrating profiles of the delivered radionuclides.

MIRD Pamphlet No. 27: MIRDcell V3, a Revised Software Tool for Multicellular Dosimetry and Bioeffect Modeling.

Radiopharmaceutical therapy is growing rapidly. However, yet to be addressed is the implementation of methods to plan treatments for circulating tumor cells, disseminated tumor cells, and micrometastases. Given the capacity of radiopharmaceuticals to specifically target and kill single cells and multicellular clusters, a quality not available in chemotherapy and external-beam radiation therapy, it is important to develop dosimetry and bioeffect modeling tools that can inform radiopharmaceutical design and predict their effect on microscopic disease. This pamphlet describes a new version of MIRDcell, a software tool that was initially released by the MIRD committee several years ago. Methods: Version 3 (V3) of MIRDcell uses a combination of analytic and Monte Carlo methods to conduct dosimetry and bioeffect modeling for radiolabeled cells within planar colonies and multicellular clusters. A worked example is provided to assist users to learn old and new features of MIRDcell and test its capacity to recapitulate published responses of tumor cell spheroids to radiopharmaceutical treatments. Prominent capabilities of the new version include radially dependent activity distributions, user-imported activity distributions, cold regions within the cluster, complex bioeffect modeling that accounts for radiation type and subcellular distribution, and a rich table of output data for subsequent analysis. Results: MIRDcell V3 effectively reproduces experimental responses of multicellular spheroids to uniform and nonuniform distributions of therapeutic radiopharmaceuticals. Conclusion: MIRDcell is a versatile software tool that can be used for educational purposes and design of radiopharmaceutical therapies.

Radiation biology workforce in the United States.

In recent decades, the principal goals of participants in the field of radiation biologists have included defining dose thresholds for cancer and non-cancer endpoints to be used by regulators, clinicians and industry, as well as informing on best practice radiation utilization and protection applications. Importantly, much of this work has required an intimate relationship between "bench" radiation biology scientists and their target audiences (such as physicists, medical practitioners and epidemiologists) in order to ensure that the requisite gaps in knowledge are adequately addressed. However, despite the growing risk for public exposure to higher-than-background levels of radiation, e.g. from long-distance travel, the increasing use of ionizing radiation during medical procedures, the threat from geopolitical instability, and so forth, there has been a dramatic decline in the number of qualified radiation biologists in the U.S. Contributing factors are thought to include the loss of applicable training programs, loss of jobs, and declining opportunities for advancement. This report was undertaken in order to begin addressing this situation since inaction may threaten the viability of radiation biology as a scientific discipline.

Radium-223 dichloride causes transient changes in natural killer cell population and cytotoxic function.

RATIONALE: Natural killer (NK) cells play an important role in both the innate and adaptive arms of the immune system. While previous studies have demonstrated the effects of ionizing radiation on cytotoxic function of NK cells, little is known about how a chronic exposure to high LET alpha particles emitted by radionuclides will affect both NK population size and function. This study was conducted to determine the effects of 223RaCl2 on splenic NK cell population size and function in Swiss Webster mice. METHODS: Swiss Webster mice were administered intravenously with 0, 50, or 600 kBq/kg 223RaCl2. Spleens were harvested at 5, 12, and 19 days post-administration. The numbers of splenocytes per spleen were enumerated and flow cytometry was used to assess changes in the distribution of splenocyte subpopulations of B, CD4 and CD8 T lymphocytes, and NK cells. NK functional activity was quantified using YAC-1 target cells and the 51Cr-release assay. RESULTS: The total number of splenocytes was unaffected by 223RaCl2. However, significant changes in the distribution of splenocyte subpopulations were observed for NK cells and CD8 T lymphocytes. NK functional activity was enhanced substantially relative to controls at 12 days post-administration, but decreased markedly by day 19. CONCLUSION: NK functional activity is both diminished and enhanced by 223RaCl2 depending on both administered activity and time post-administration. These results suggest that there may be an optimum window of time to combine the 223RaCl2-induced antitumor NK cell response with other cancer therapies that elicit immune activation.

Modeling bystander effects that cause growth delay of breast cancer xenografts in bone marrow of mice treated with radium-223.

RATIONALE: The role of radiation-induced bystander effects in cancer therapy with alpha-particle emitting radiopharmaceuticals remains unclear. With renewed interest in using alpha-particle emitters to sterilize disseminated tumor cells, micrometastases, and tumors, a better understanding of the direct effects of alpha particles and the contribution of the bystander responses they induce is needed to refine dosimetric models that help predict clinical benefit. Accordingly, this work models and quantifies the relative importance of direct effects (DE) and bystander effects (BE) in the growth delay of human breast cancer xenografts observed previously in the tibiae of mice treated with 223RaCl2. METHODS: A computational model of MDA-MB-231 and MCF-7 human breast cancer xenografts in the tibial bone marrow of mice administered 223RaCl2 was created. A Monte Carlo radiation transport simulation was performed to assess individual cell absorbed doses. The responses of the breast cancer cells to direct alpha particle irradiation and gamma irradiation were needed as input data for the model and were determined experimentally using a colony-forming assay and compared to the responses of preosteoblast MC3T3-E1 and osteocyte-like MLO-Y4 bone cells. Using these data, a scheme was devised to simulate the dynamic proliferation of the tumors in vivo, including DE and BE propagated from the irradiated cells. The parameters of the scheme were estimated semi-empirically to fit experimental tumor growth. RESULTS: A robust BE component, in addition to a much smaller DE component, was required to simulate the in vivo tumor proliferation. We also found that the relative biological effectiveness (RBE) for cell killing by alpha particle radiation was greater for the bone cells than the tumor cells. CONCLUSION: This modeling study demonstrates that DE of radiation alone cannot explain experimental observations of 223RaCl2-induced growth delay of human breast cancer xenografts. Furthermore, while the mechanisms underlying BE remain unclear, the addition of a BE component to the model is necessary to provide an accurate prediction of the growth delay. More complex models are needed to further comprehend the extent and complexity of 223RaCl2-induced BE.

Radium-223-Induced Bystander Effects Cause DNA Damage and Apoptosis in Disseminated Tumor Cells in Bone Marrow.

Radiation-induced bystander effects have been implicated in contributing to the growth delay of disseminated tumor cells (DTC) caused by 223RaCl2, an alpha particle-emitting radiopharmaceutical. To understand how 223RaCl2 affects the growth, we have quantified biological changes caused by direct effects of radiation and bystander effects caused by the emitted radiations on DTC and osteocytes. Characterizing these effects contribute to understanding the efficacy of alpha particle-emitting radiopharmaceuticals and guide expansion of their use clinically. MDA-MB-231 or MCF-7 human breast cancer cells were inoculated intratibially into nude mice that were previously injected intravenously with 50 or 600 kBq/kg 223RaCl2. At 1-day and 3-days postinoculation, tibiae were harvested and examined for DNA damage (γ-H2AX foci) and apoptosis in osteocytes and cancer cells located within and beyond the range (70 µm) of alpha particles emitted from the bone surface. Irradiated and bystander MDA-MB-231 and MCF-7 cells harbored DNA damage. Bystander MDA-MB-231 cells expressed DNA damage at both treatment levels while bystander MCF-7 cells required the higher administered activity. Osteocytes also had DNA damage regardless of inoculated cancer cell line. The extent of DNA damage was quantified by increases in low (1-2 foci), medium (3-5 foci), and high (5+ foci) damage. MDA-MB-231 but not MCF-7 bystander cells showed increases in apoptosis in 223RaCl2-treated animals, as did irradiated osteocytes. In summary, radiation-induced bystander effects contribute to DTC cytotoxicity caused by 223RaCl2. IMPLICATIONS: This observation supports clinical investigation of the efficacy of 223RaCl2 to prevent breast cancer DTC from progressing to oligometastases.

Acquired radioresistance in cancer associated fibroblasts is concomitant with enhanced antioxidant potential and DNA repair capacity.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are a major component of the cancer stroma, and their response to therapeutic treatments likely impacts the outcome. We tested the hypothesis that CAFs develop unique characteristics that enhance their resistance to ionizing radiation. METHODS: CAFs were generated through intimate coculture of normal human fibroblasts of skin or lung origin with various human cancer cell types using permeable microporous membrane inserts. Fibroblasts and cancer cells are grown intimately, yet separately, on either side of the insert's membrane for extended times to generate activated fibroblast populations highly enriched in CAFs. RESULTS: The generated CAFs exhibited a decrease in Caveolin-1 protein expression levels, a CAF biomarker, which was further enhanced when the coculture was maintained under in-vivo-like oxygen tension conditions. The level of p21Waf1 was also attenuated, a characteristic also associated with accelerated tumor growth. Furthermore, the generated CAFs experienced perturbations in their redox environment as demonstrated by increases in protein carbonylation, mitochondrial superoxide anion levels, and modulation of the activity of the antioxidants, manganese superoxide dismutase and catalase. Propagation of the isolated CAFs for 25 population doublings was associated with enhanced genomic instability and a decrease in expression of the senescence markers ß-galactosidase and p16INK4a. With relevance to radiotherapeutic treatments, CAFs in coculture with cancer cells of diverse origins (breast, brain, lung, and prostate) were resistant to the clastogenic effects of 137Cs γ rays compared to naïve fibroblasts. Addition of repair inhibitors of single- or double-stranded DNA breaks attenuated the resistance of CAFs to the clastogenic effects of γ rays, supporting a role for increased ability to repair DNA damage in CAF radioresistance. CONCLUSIONS: This study reveals that CAFs are radioresistant and experience significant changes in indices of oxidative metabolism. The CAFs that survive radiation treatment likely modulate the fate of the associated cancer cells. Identifying them together with their mode of communication with cancer cells, and eradicating them, particularly when they may exist at the margin of the radiotherapy planning target volume, may improve the efficacy of cancer treatments. Video Abstract.

Overview of the First NRG Oncology-National Cancer Institute Workshop on Dosimetry of Systemic Radiopharmaceutical Therapy.

In 2018, the National Cancer Institute and NRG Oncology partnered for the first time to host a joint workshop on systemic radiopharmaceutical therapy (RPT) to specifically address dosimetry issues and strategies for future clinical trials. The workshop focused on current dosimetric approaches for clinical trials, strategies under development that would optimize dose reporting, and future desired or optimized approaches for novel emerging radionuclides and carriers in development. In this article, we review the main approaches that are applied clinically to calculate the absorbed dose. These include absorbed doses calculated over a variety of spatial scales, including whole body, organ, suborgan, and voxel, the last 3 of which are achievable within the MIRD schema (S value) and can be calculated with analytic methods or Monte Carlo methods, the latter in most circumstances. This article will also contrast currently available methods and tools with those used in the past, to propose a pathway whereby dosimetry helps the field by optimizing the biologic effect of the treatment and trial design in the drug approval process to reduce financial and logistical costs. We also briefly discuss the dosimetric equivalent of biomarkers to help bring a precision medicine approach to RPT implementation when merited by evidence collected during early-phase trial investigations. Advances in the methodology and related tools have made dosimetry the optimum biomarker for RPT.

Dose-Dependent Growth Delay of Breast Cancer Xenografts in the Bone Marrow of Mice Treated with 223Ra: The Role of Bystander Effects and Their Potential for Therapy.

The role of radiation-induced bystander effects in radiation therapy remains unclear. With renewed interest in therapy with α-particle emitters, and their potential for sterilizing disseminated tumor cells (DTCs), it is critical to determine the contribution of bystander effects to the overall response so they can be leveraged for maximum clinical benefit. Methods: Female Foxn1nu athymic nude mice were administered 0, 50, or 600 kBq/kg 223RaCl2 to create bystander conditions. At 24 hours after administration, MDA-MB-231 or MCF-7 human breast cancer cells expressing luciferase were injected into the tibial marrow compartment. Tumor burden was tracked weekly via bioluminescence. Results: The MDA-MB-231 xenografts were observed to have a 10-day growth delay in the 600 kBq/kg treatment group only. In contrast, MCF-7 cells had 7- and 65-day growth delays in the 50 and 600 kBq/kg groups, respectively. Histologic imaging of the tibial marrow compartment, α-camera imaging, and Monte Carlo dosimetry modeling revealed DTCs both within and beyond the range of the α-particles emitted from 223Ra in bone for both MCF-7 and MDA-MB-231 cells. Conclusion: Taken together, these results support the participation of 223Ra-induced antiproliferative/cytotoxic bystander effects in delayed growth of DTC xenografts. They indicate that the delay depends on the injected activity and therefore is dose-dependent. They suggest using 223RaCl2 as an adjuvant treatment for select patients at early stages of breast cancer.

A preliminary study on treatment of human breast cancer xenografts with a cocktail of paclitaxel, doxorubicin, and 131I-anti-epithelial cell adhesion molecule (9C4).

Triple-negative breast cancer often has devastating outcomes and treatment options remain limited. Therefore, different treatment combinations are worthy of testing. The efficacy of a cocktail of paclitaxel, doxorubicin, and 131I-anti-epithelial cell adhesion molecule (EpCAM) (9C4) to treat breast cancer was tested. Efficacy was tested with an MDA-MB-231 human breast cancer xenograft model. Anti-EpCAM (9C4) was demonstrated to bind to MDA-MB-231 human adenocarcinoma cells in vitro. Subsequently, mice-bearing MDA-MB-231× enografts were treated with either 131I-anti-EpCAM (9C4), unlabeled anti-EpCAM (9C4), paclitaxel, doxorubicin, or a cocktail of all of the agents. Tumor volume was measured for up to 70-day postinjection. Exponential regression was performed on tumor growth curves for each of the therapy groups. Statistical comparison of the growth constants λ of the regression models for each of the treatment groups with that of the cold antibody and control groups was done using extra sum-of-square F-tests. Biexponential clearance of 131I-anti-EpCAM (9C4) was observed with biological clearance half-times of 1.14 and 17.6 days for the first and second components, respectively. The mean growth rate of the tumors in animals treated with a cocktail of all of the agents was slower than in those treated with unlabeled anti-EpCAM (9C4) (P = 0.022). These preliminary data suggest that a cocktail of 131I-anti-EpCAM (9C4), paclitaxel, and doxorubicin may be suitable for treating breast cancers with high expression of EpCAM.

Design and testing of a microcontroller that enables alpha particle irradiators to deliver complex dose rate patterns.

There is increasing interest in using alpha particle emitting radionuclides for cancer therapy because of their unique cytotoxic properties which are advantageous for eradicating tumor cells. The high linear energy transfer (LET) of alpha particles produces a correspondingly high density of ionizations along their track. Alpha particle emitting radiopharmaceuticals deposit this energy in tissues over prolonged periods with complex dose rate patterns that depend on the physical half-life of the radionuclide, and the biological uptake and clearance half-times in tumor and normal tissues. We have previously shown that the dose rate increase half-time that arises as a consequence of these biokinetics can have a profound effect on the radiotoxicity of low-LET radiation. The microcontroller hardware and software described here offer a unique way to deliver these complex dose rate patterns with a broad-beam alpha particle irradiator, thereby enabling experiments to study the radiobiology of complex dose rate patterns of alpha particles. Complex dose rate patterns were created by precise manipulation of the timing of opening and closing of the electromechanical shutters of an α-particle irradiator. An Arduino Uno and custom circuitry was implemented to control the shutters. The software that controls the circuits and shutters has a user-friendly Graphic User Interface (GUI). Alpha particle detectors were used to validate the programmed dose rate profiles. Circuit diagrams and downloadable software are provided to facilitate adoption of this technology by other radiobiology laboratories.

A model for optimizing delivery of targeted radionuclide therapies into resection cavity margins for the treatment of primary brain cancers.

Radionuclides conjugated to molecules that bind specifically to cancer cells are of great interest as a means to increase the specificity of radiotherapy. Currently, the methods to disseminate these targeted radiotherapeutics have been either systemic delivery or by bolus injection into the tumor or tumor resection cavity. Herein we model a potentially more efficient method of delivery, namely pressure-driven fluid flow, called convection-enhanced delivery (CED), where a device infuses the molecules in solution (or suspension) directly into the tissue of interest. In particular, we focus on the setting of primary brain cancer after debulking surgery, where the tissue margins surrounding the surgical resection cavity are infiltrated with tumor cells and the most frequent sites of tumor recurrence. We develop the combination of fluid flow, chemical kinetics, and radiation dose models needed to examine such protocols. We focus on Auger electron-emitting radionuclides (e.g. 67Ga, 77Br, 111In, 125I, 123I, 193mPt, 195mPt) whose short range makes them ideal for targeted therapy in this setting of small foci of tumor spread within normal tissue. By solving these model equations, we confirm that a CED protocol is promising in allowing sufficient absorbed dose to destroy cancer cells with minimal absorbed dose to normal cells at clinically feasible activity levels. We also show that Auger emitters are ideal for this purpose while the longer range alpha particle emitters fail to meet criteria for effective therapy (as neither would energetic beta particle emitters). The model is used with simplified assumptions on the geometry and homogeneity of brain tissue to allow semi-analytic solutions to be displayed, and with the purpose of a first examination of this new delivery protocol proposed for radionuclide therapy. However, we emphasize that it is immediately extensible to personalized therapy treatment planning as we have previously shown for conventional CED, at the price of requiring a fully numerical computerized approach.

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

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/ß) 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/ß 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/ß 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.