Wouters, B. G. & Brown, J. M. Cells at intermediate oxygen levels can be more important than the hypoxic fraction in determining tumor response to fractionated radiotherapy. Radiat. Res. 147, 541-550

Department of Radiation Oncology, Stanford University School of Medicine, California 94305-5468, USA.
Radiation Research (Impact Factor: 2.91). 06/1997; 147(5):541-50. DOI: 10.2307/3579620
Source: PubMed


The presence of hypoxic cells in human tumors is thought to be one of the principal reasons for the failure of radiation therapy. Intensive laboratory and clinical efforts to overcome tumor hypoxia have focused on oxygenating, radiosensitizing or killing the maximally radioresistant fraction of tumor cells. This "hypoxic fraction" dominates the single-dose radiation response, irrespective of the oxygenation status of the remainder of the tumor cell population. However, at doses that are typical of those delivered in a daily radiotherapy protocol, we show that the tumor response is highly dependent upon the cells at oxygen levels intermediate between fully oxygenated and hypoxic (0.5-20 mm Hg). For most tumors, these cells are more important than the radiobiologically hypoxic cells in determining treatment outcome after 30 fractions of 2 Gy. We also show that under conditions of diffusion-limited hypoxia, the impact of full reoxygenation between fractions is much smaller than previously realized. Together, the results imply that tumor hypoxia plays a more significant role in determining the outcome of fractionated radiotherapy than previous measurements and assumptions of hypoxic fractions have indicated. Therefore, the concept of a hypoxic fraction in human tumors is less meaningful when pertaining to a fractionated radiotherapy regimen, and should not be expected to be useful for predicting tumor responses in the clinic. This implies the need to characterize tumor oxygenation in a manner that reflects the true oxygenation status of all the tumor cells, not just the ones most refractory to the effects of ionizing radiation. Furthermore, effective therapeutic agents must have the ability to specifically sensitize or kill those cells at intermediate levels of oxygen in addition to the radiobiologically hypoxic cells.

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    • "Alternative modeling approaches were based on ODE (Ordinary Differential Equation) and PDE (Partial Differential Equation) and included dead/inactivated cell kinetics [14], the effects of oxygenation [1], [3], [15], [16], and different microenvironment conditions [12]. Early studies reported that the radioresponsiveness of homogenous cell lines can sensibly vary as a function of many factors, such as cancer volume size, level of oxygenation, vascularization, and delivered dose [17], [18], with a general consensus that the larger the volume size is, the smaller the cell killing rate is expected to be, due to larger hypoxia effects [19]. Furthermore, it was shown that reoxygenation may occur because of tumor shrinkage, decreased oxygen consumption, and increased perfusion [15],[16]. "
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    ABSTRACT: This paper describes a patient-specific mathematical model to predict the evolution of uterine cervical tumors at a macroscopic scale, during fractionated external radiotherapy. The model provides estimates of tumor re-growth and dead-cell reabsorption, incorporating the interplay between tumor regression rate and radiosensitivity, as a function of the tumor oxygenation level. Model parameters were estimated by minimizing the difference between predicted and measured tumor volumes, these latter being obtained from a set of 154 serial cone-beam computed tomography (CBCT) scans acquired on 16 patients along the course of the therapy. The model stratified patients according to two different estimated dynamics of dead-cell removal and to the predicted initial value of the tumor oxygenation. The comparison with a simpler model demonstrated an improvement in fitting properties of this approach (fitting error average value <5%, p<0.01), especially in case of tumor late responses, which can hardly be handled by models entailing a constant radiosensitivity, failing to model changes from initial severe hypoxia to aerobic conditions during the treatment course. The model predictive capabilities suggest the need of clustering patients accounting for cancer cell-line, tumor staging, as well as microenvironment conditions (e.g. oxygenation level).
    IEEE Journal of Biomedical and Health Informatics 01/2015; DOI:10.1109/JBHI.2015.2398512 · 1.44 Impact Factor
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    • "The results suggest that the total number of metabolically viable hypoxic cells (in I-compartment of the model) is a deterministic factor in tumor response and this subpopulation might be associated with the voxel-by-voxel correlation studies performed by Pugachev et al. [16] and Rajendran et al. [15], in which the microregional relationship between FDG and hypoxia was observed. Also the result supports the study of Wouters and Brown, in which the importance of the cells at intermediate oxygen level was emphasized [26]. "
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    ABSTRACT: High fluorodeoxyglucose positron emission tomography (FDG-PET) uptake in tumors has often been correlated with increasing local failure and shorter overall survival, but the radiobiological mechanisms of this uptake are unclear. We explore the relationship between FDG-PET uptake and tumor radioresistance using a mechanistic model that considers cellular status as a function of microenvironmental conditions, including proliferating cells with access to oxygen and glucose, metabolically active cells with access to glucose but not oxygen, and severely hypoxic cells that are starving. However, it is unclear what the precise uptake levels of glucose should be for cells that receive oxygen and glucose versus cells that only receive glucose. Different potential FDG uptake profiles, as a function of the microenvironment, were simulated. Predicted tumor doses for 50% control (TD50) in 2 Gy fractions were estimated for each assumed uptake profile and for various possible cell mixtures. The results support the hypothesis of an increased avidity of FDG for cells in the intermediate stress state (those receiving glucose but not oxygen) compared to well-oxygenated (and proliferating) cells.
    Computational and Mathematical Methods in Medicine 09/2014; 2014:847162. DOI:10.1155/2014/847162 · 0.77 Impact Factor
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    • "Theoretical simulations using (9)–(13) have shown significant differences in the predicted response depending on the assumed oxygenation of the tissue and these results indicate that full distributions of pO2 values, not only the hypoxic fraction, are needed for modelling [25, 56, 63]. This is particularly important in light of the equivocal relationship between tumour oxygenation and the above-mentioned parameters. "
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    ABSTRACT: Oxygenation is an important component of the tumour microenvironment, having a significant impact on the progression and management of cancer. Theoretical determination of tissue oxygenation through simulations of the oxygen transport process is a powerful tool to characterise the spatial distribution of oxygen on the microscopic scale and its dynamics and to study its impact on the response to radiation. Accurate modelling of tumour oxygenation must take into account important aspects that are specific to tumours, making the quantitative characterisation of oxygenation rather difficult. This paper aims to discuss the important aspects of modelling tumour oxygenation, reoxygenation, and implications for treatment.
    Computational and Mathematical Methods in Medicine 01/2013; 2013:141087. DOI:10.1155/2013/141087 · 0.77 Impact Factor
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