Hypofractionation results in reduced tumor cell kill compared to conventional fractionation for tumors with regions of hypoxia

Abstract

Purpose: Tumor hypoxia has been observed in many human cancers and is associated with treatment failure in radiation therapy. The purpose of this study is to quantify the effect of different radiation fractionation schemes on tumor cell killing, assuming a realistic distribution of tumor oxygenation.

Methods and materials: A probability density function for the partial pressure of oxygen in a tumor cell population is quantified as a function of radial distance from the capillary wall. Corresponding hypoxia reduction factors for cell killing are determined. The surviving fraction of a tumor consisting of maximally resistant cells, cells at intermediate levels of hypoxia, and normoxic cells is calculated as a function of dose per fraction for an equivalent tumor biological effective dose under normoxic conditions.

Results: Increasing hypoxia as a function of distance from blood vessels results in a decrease in tumor cell killing for a typical radiotherapy fractionation scheme by a factor of 10(5) over a distance of 130 μm. For head-and-neck cancer and prostate cancer, the fraction of tumor clonogens killed over a full treatment course decreases by up to a factor of ∼10(3) as the dose per fraction is increased from 2 to 24 Gy and from 2 to 18 Gy, respectively.

Conclusions: Hypofractionation of a radiotherapy regimen can result in a significant decrease in tumor cell killing compared to standard fractionation as a result of tumor hypoxia. There is a potential for large errors when calculating alternate fractionations using formalisms that do not account for tumor hypoxia.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Figure 1

Oxygen partial pressure as a function of radial distance from the center of a capillary. The solid line represents the assumed oxygen diffusion parameters that result in an average oxygen partial pressure of ~ 6.9 mmHg.

Figure 2

Hypoxia reduction factor (HRF) values derived from published cell survival data (11, 15, 26, 27). Solid line shows a fit to the values using Eq. (4) with m = 2.8 and K = 1.5.

Figure 3

Surviving fraction of tumor clonogens as a function of radial distance from the capillary center for conventional radiotherapy fractionations.

Figure 4

Total surviving fraction of tumor clonogens as a function of dose per fraction assuming daily fractionation and full reoxygenation between fractions. Dependence of model predictions on the assumed value of the hypoxic fraction of cells is shown.

Figure 5

Total surviving fraction of tumor clonogens as a function of dose per fraction assuming daily fractionation and full reoxygenation between fractions. Dependence of model predictions on intrafraction DSB repair and clonogen repopulation is shown.

Figure 6

Sensitizer enhancements ratio (SER) values derived from published cell survival data (15). Solid lines shows a fit to the values using Eq. (10) with x = 1.4 and y = 0.4 for the 1.2 mM concentration and x = 2.0 and y = 0.9 for the 5.0 mM concentration.

Figure 7

Effect of misonidazole and radiation on surviving fraction of tumor clonogens assuming a realistic distribution of tumor hypoxia, intrafraction DSB repair, and clonogen repopulation. Dotted lines show predictions neglecting corrections for hypoxia, repair, and repopulation.