Purpose To demonstrate that a mathematical model can be used to quantitatively understand tumor cellular dynamics during a course of radiotherapy, and to predict the likelihood of local control as a function of dose and treatment fractions. Experimental Design We model outcomes for early-stage, localized non-small cell lung cancer (NSCLC), by fitting a mechanistic, cellular dynamics-based tumor control probability that assumes a constant local supply of oxygen and glucose. In addition to standard radiobiological effects such as repair of sub-lethal damage and the impact of hypoxia, we also accounted for proliferation as well as radiosensitivity variability within the cell cycle. We applied the model to 36 published and 2 unpublished early stage patient cohorts, totaling 2701 patients. Results Precise likelihood best-fit values were derived for the radiobiological parameters: α (0.305 Gy-1; 95% CI: 0.120-0.365), the α/β ratio (2.80 Gy; 95% CI: 0.40-4.40), and the oxygen enhancement ratio (OER) value for intermediately hypoxic cells receiving glucose but not oxygen (1.70; 95% CI: 1.55-2.25). All fractionation groups are well-fitted by a single dose-response curve with a high χ2 p-value, indicating consistency with the fitted model. The analysis was further validated with an additional 23 patient cohorts (n=1628). The model indicates that hypofractionation regimens overcome hypoxia (and cell-cycle radiosensitivity variations) by the sheer impact of high doses per fraction, whereas lower dose-per-fraction regimens allow for reoxygenation and corresponding sensitization, but lose effectiveness for prolonged treatments due to proliferation. Conclusions This proposed mechanistic tumor-response model can accurately predict over-treatment or under-treatment for various treatment regimens.

A tumour control probability computational model for fractionated radiotherapy was developed, with the goal of incorporating the fundamental interplay between hypoxia and proliferation, including reoxygenation over a course of radiotherapy. The fundamental idea is that the local delivery of oxygen and glucose limits the amount of proliferation and metabolically-supported cell survival a tumour sub-volume can support. The model has three compartments: a proliferating compartment of cells receiving oxygen and glucose; an intermediate, metabolically-active compartment receiving glucose; and a highly hypoxic compartment of starving cells. Following the post-mitotic cell death of proliferating cells, intermediate cells move into the proliferative compartment and hypoxic cells move into the intermediate compartment. A key advantage of the proposed model is that the initial compartmental cell distribution is uniquely determined from the assumed local growth fraction (GF) and volume doubling time (TD) values. Varying initial cell state distributions, based on the local (voxel) GF and TD, were simulated. Tumour response was simulated for head and neck squamous cell carcinoma using relevant parameter values based on published sources. The tumour dose required to achieve a 50% local control rate (TCD50) was found for various GFs and TD’s, and the effect of fraction size on TCD50 was also evaluated. Due to the advantage of reoxygenation over a course of radiotherapy, conventional fraction sizes (2–2.4 Gy fx−1) were predicted to result in smaller TCD50’s than larger fraction sizes (4–5 Gy fx−1) for a 10 cc tumour with GFs of around 0.15. The time to eliminate hypoxic cells (the reoxygenation time) was estimated for a given GF and decreased as GF increased. The extra dose required to overcome accelerated stem cell accumulation in longer treatment schedules was estimated to be 0.68 Gy/day (in EQD26.6), similar to published values derived from clinical data. The model predicts, for a 2 Gy/weekday fractionation, that increased initial proliferation (high GF) should, surprisingly, lead to moderately higher local control values. Tumour hypoxia is predicted to increase the required dose for local control by approximately 30%. Predicted tumour regression patterns are consistent with clinical observations. This simple yet flexible model shows how the local competition for chemical resources might impact local control rates under varying fractionation conditions.

Background and purpose Although FDG-avid tumors are recognized as a potential target for dose escalation, there is no clear basis for selecting a boost dose to counter this apparent radioresistance. Using a novel analysis method, based on the new concept of an outcome-equivalent dose, we estimate the extra dose required to equalize local control between FDG-avid and non-avid head and neck tumors. Materials and methods Based on a literature review, five reports of head and neck cancer (423 patients in total), along with an internal validation dataset from our institution (135 oropharynx patients), were used in this analysis. To compensate for the heterogeneity among multi-institutional patient cohorts and corresponding treatment techniques, local control data of the cohorts were fit to a single dose–response curve with a clinically representative steepness (γ50 = 2), thereby defining an ‘outcome-equivalent dose’ (OED) for each institutional cohort. Separate dose–response curves were then determined for the FDG-avid and FDG-non-avid patient cohorts, and the ratio of TD50 (tumor dose required for 50% of control) values between the high- and low-FDG-uptake groups (TD50,high/TD50,low) was estimated, resulting in an estimated metabolic dose-modifying factor (mDMF) due to FDG-avidity. Results For individual datasets, the estimated mDMFs were found to be in the range of 1.07–1.62, decreasing if the assumed slope (γ50) increased. Weighted logistic regression for the six datasets resulted in a mDMF of 1.19 [95% CI: 1.04–1.34] for a γ50 value of 2, which translates to a needed dose increase of about 1.5 Gy per unit increase in the maximum standardized uptake value (SUVm) of FDG-PET [95% CI: 0.3–2.7]. Assumptions of lower or higher γ50 values (1.5 or 2.5) resulted in slightly different mDMFs: 1.26 or 1.15, respectively. A validation analysis with seven additional datasets, based on relaxed criteria, was consistent with the estimated mDMF. Conclusions We introduced a novel outcome-equivalent dose analysis method to estimate the dose– response modifying effect of FDG uptake variation. To reach equal response rates, FDG-avid tumors are likely to require 10% to 30% more dose than FDG-non-avid tumors. These estimates provide a rational starting point for selecting IMRT boosts for FDG-avid tumors. However, independent tests and refinements of the estimated dose-modifying effect, using high-quality prospective clinical trial data, are needed.

Radiation-induced gastrointestinal syndrome (RIGS) is a limiting factor for therapeutic abdominopelvic radiation and is predicted to be a major source of morbidity in the event of a nuclear accident or radiological terrorism. In this study, we developed an in vivo mouse-modeling platform that enables spatial and temporal manipulation of potential RIGS targets in mice following whole-abdomen irradiation without the confounding effects of concomitant hematopoietic syndrome that occur following whole-body irradiation. We then tested the utility of this platform to explore the effects of transient Wnt pathway activation on intestinal regeneration and animal recovery following induction of RIGS. Our results demonstrate that intestinal epithelial suppression of adenomatous polyposis coli (Apc) mitigates RIGS lethality in vivo after lethal ionizing radiation injury-induced intestinal epithelial damage. These results highlight the potential of short-term Wnt agonism as a therapeutic target and establish a platform to evaluate other strategies to stimulate intestinal regeneration after ionizing radiation damage.

Purpose To evaluate the feasibility of delivering experimental radiotherapy to tumors in the mouse pancreas. Imaging and treatment were performed using combined CT (computed tomography)/orthovoltage treatment with a rotating gantry. Methods and Materials After intraperitoneal administration of radiopaque iodinated contrast, abdominal organ delineation was performed by X-ray CT. With this technique we delineated the pancreas, and both orthotopic xenografts and genetically engineered disease. CT imaging was validated by comparison with magnetic resonance (MR) imaging. Therapeutic radiation was delivered via a 1 cm diameter field. Selective X-ray radiation therapy (XRT) of the non-invasively defined orthotopic mass was confirmed using γH2AX staining. Mice could tolerate a dose of 15 Gy when the field was centered on the pancreas tail, and treatment was delivered as a continuous 360-degree arc. This strategy was then used for radiation therapy planning for selective delivery of therapeutic XRT to orthotopic tumors. Results Tumor growth delay after 15 Gy was monitored, using CT and ultrasound to determine the tumor volume at various times post-treatment. Our strategy enables the use of clinical radiation oncology approaches to treat experimental tumors in the pancreas of small animals for the first time. We demonstrate that delivery of 15 Gy from a rotating gantry minimizes background healthy tissue damage and significantly retards tumor growth. Conclusions This advance permits evaluation of radiation planning and dosing parameters. Accurate non-invasive longitudinal imaging and monitoring of tumor progression and therapeutic response in pre-clinical models is now possible, and can be expected to more effectively evaluate pancreatic cancer disease and therapeutic response.