Predicting the effect of temporal variations in po2 on tumor radiosensitivity

doi:10.1016/j.ijrobp.2004.02.015

International Journal of Radiation OncologyBiologyPhysics

Volume 59, Issue 3, 1 July 2004, Pages 822-833

Presented in part at the 44th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, October 10–14, 2002.

https://doi.org/10.1016/j.ijrobp.2004.02.015 Get rights and content

Abstract

Purpose

Tumor hypoxia is associated with less effective radiation-mediated cell killing, increased metastatic potential, and poorer prognosis. Transient variations in hypoxia, with characteristic periodicity on the order of 1 to 10 min, have been observed in animal models. This article explores the effect of these temporal variations in Po₂ on the oxygen enhancement ratio, effective radiation dose to the tumor, and tumor control probability.

Methods and materials

Po₂ over a 50–60 min period was determined at multiple sites in rat fibrosarcomas, 9L gliomas, and R3230Ac mammary adenocarcinomas. Using a correlation derived from the data of Elkind et al. (1965), Po₂ data are converted into oxygen enhancement ratios (OERs.) A tumor is assumed to consist of 10³–10⁴ independent oxygenation subvolumes, each with a randomly chosen starting point on the OER-time curve. The effect of temporal variations in OER is examined for three cases: conventionally fractionated external beam radiotherapy (EBRT), stereotactic radiosurgery (SRS) and intraoperative radiotherapy (IORT). The oxygen effective dose (OED) for a subvolume is calculated from the dose to that subvolume modified by the OER. In turn, the distribution of OED for a tumor is analyzed for each treatment case and representative tumor control probabilities (TCPs) calculated.

Results

Oxygen enhancement ratio varied from 1 to 3 over the range of Po₂ measured in this study. Mean OER ranged from 1.6 to 2.6, and the variation in OER vs. time was greater with decreasing Po₂. In EBRT, the standard deviation in OED was small, <2%. In contrast, the standard deviation in OED was much higher for both SRS and IORT, typically ranging from 3 to 6%, with the greatest variation at the lowest Po₂s. Compared with a tumor with equal mean OED and uniform Po₂, TCP was minimally poorer for either EBRT or well-oxygenated tumors. However, for both SRS and IORT, temporal variations in more hypoxic tumors can produce a significant decrease in TCP.

Conclusion

Temporal variations in tumor Po₂ can produce significant variations OER, particularly at low Po₂, resulting in decreased TCP for hypofractionated treatment regimens.

Introduction

More than 50 years ago, oxygen was demonstrated to enhance the radiosensitivity of tumor cells (1), and this effect has been confirmed in numerous cell lines and animal models 2, 3, 4, 5. In addition, low oxygen tension (Po₂) has been shown to promote the selection of cells with reduced apoptotic potential (6), to induce genes promoting angiogenesis (7), and to increase the frequency of mutations (8). In cancer patients, tumor hypoxia is associated with increased metastases, decreased progression-free survival, and poorer outcome 9, 10, 11, 12, 13, 14, 15.

Tumor hypoxia is often classified as “chronic” or “acute.” Typically, chronic hypoxia (i.e., low Po₂ persisting over a period of hours to days in a subregion of a tumor) is thought to be due to the net balance of distance to the nearest capillary, the oxygen content, and blood flow in that capillary and oxygen metabolism (16). Although the primary cause of chronic hypoxia is frequently stated to be “diffusion-limited” oxygen transport (17), tissue oxygen demand and longitudinal oxygen gradients play a critical role in determining the extent and location of the hypoxic subvolumes 16, 18, 19, 20. Acute hypoxia (i.e., transient low Po₂ over the time frame of minutes to tens of minutes) is attributed to intermittent decreases in capillary blood flow resulting from vasoconstriction or reduced red blood cell flux 21, 22, 23, 24, 25, 26. Whatever the cause, temporal variations in tumor Po₂ have been observed in rodent tumors 27, 28, 29, 30, 31, 32. The time scale over which these occur has typically been thought to be a few cycles per hour, although recent data also point to the possibility of fluctuations occurring over periods of hours to days (32).

Given sufficient variation in tumor Po₂, particularly at low oxygen tensions, we would expect significant fluctuations in the oxygen enhancement ration within a tumor. In turn, these fluctuations might impair radiation-induced tumor cell kill, reducing the probability of tumor control. The radiobiologic consequences of fluctuant oxygenation have not been quantified previously in the context of specific radiation fractionation schemes. In this article, we use experimental Po₂ data as a function of time to calculate the probable distribution of oxygen enhancement ratios within a tumor. Then, in a manner similar to estimations of tumor control probability in the presence of spatial Po₂ variations (33), we explore the impact of these temporal Po₂ variations on tumor cell killing for various radiation treatment regimens. For the purposes of these simulations, the focus is on the impact of fluctuations occurring over the time scale of minutes to an hour.

Section snippets

Tumor oxygenation measurement

The measurement of tumor oxygenation in this rodent model is described in detail by Braun et al. (30) and Cárdenas-Navia et al. (31). Briefly, 2-mm³ tumor fragments were implanted subcutaneously in the left flank of female Fischer 344 rats and the tumor permitted to grow. Three rat tumor lines were used in these experiments: 9L glioma, R3230Ac mammary adenocarcinoma, and a fibrosarcoma. When the tumor reached a diameter of ∼1 cm, animals were anesthetized with pentobarbital 50 mg/kg

Results

Representative Po₂ tracings and the corresponding OER curves for the FSA, R3230AC, and 9L gliomas are shown in Fig. 2, Fig. 3, Fig. 4. Note that these data are a subset of an extensive collection of temporal oxygen measurements presented in a companion article by Cárdenas-Navia et al. (31). Although there is considerable variation within and between the tumor lines, all tumor lines exhibited times at which Po₂ fell below 10 mm Hg (OER <2.42). In addition, no tumor line approached a Po₂ that

Discussion

These results suggest that temporal fluctuations in Po₂ under hypoxic conditions may adversely affect radiosensitivity and thus tumor control in hypofractionated treatments, such as SRS. The effect of these temporal fluctuations on tumor control is modest when compared with potential changes in tonic Po₂ in the tumor. For example, the average Po₂ for Tumor M2 in the R3230Ac tumor (Fig. 11) is 1.54 mm Hg, corresponding to an OER of 1.74. Increasing or decreasing Po₂ by 0.25 mm Hg yields OERs of

Conclusion

Po₂ in tumors varies over the timeframe of minutes, leading to significant variation in the OER, particularly at low oxygen tensions. In turn, these variations in OER may adversely affect tumor control prob ability in hypofractionated treatment schemes, such as stereotactic radiosurgery and intraoperative radiotherapy.

Acknowledgements

The authors appreciate the gift of 9L glioma cells from Dr. Kenneth Wheeler, the IORT example provided by Ms. Beverly Steffey, and the discussions with Drs. Timothy Shafman and Lawrence Marks regarding stereotactic radiosurgery.

References (40)

G.U. Dachs et al.
Microenvironmental control of gene expressionImplications for tumor angiogenesis, progression and metastases
Semin Radiat Oncol
(1998)
D.M. Brizel et al.
Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck
Int J Radiat Oncol Biol Phys
(1997)
M. Nordsmark et al.
Pre-treatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck
Radiother Oncol
(1996)
A. Ressel et al.
Tumor oxygenation after radiotherapy, chemotherapy and/or hyperthermia predicts tumor-free survival
Int J Radiat Oncol Biol Phys
(2001)
T.W. Secomb et al.
Analysis of oxygen transport to tumor tissue by microvascular networks
Int J Radiat Oncol Biol Phys
(1993)
J. Overgaard et al.
Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and radiosensitizers
Semin Radiat Oncol
(1996)
D.J. Chaplin et al.
Acute hypoxia in tumorsImplications for modifiers of radiation effects
Int J Radiat Oncol Biol Phys
(1986)
M.W. Dewhirst et al.
Temporal changes in Po₂ of R3230Ac tumors in Fischer-344 rats
Int J Radiat Oncol Biol Phys
(1998)
R.A. Popple et al.
Tumor control probability for selective boosting of hypoxic subvolumes, including the effect of reoxygenation
Int J Radiat Oncol Biol Phys
(2002)
L.B. Harrison et al.
High dose rate intraoperative radiation therapy (HDR-IORT) as part of the management strategy for locally advanced primary and recurrent rectal cancer
Int J Radiat Oncol Biol Phys
(1998)

K.S. Chao et al.

A novel approach to overcome hypoxic tumor resistanceCu-ATSM-guided intensity-modulated radiation therapy

Int J Radiat Oncol Biol Phys

(2001)

L.H. Gray et al.

The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy

Br J Radiol

(1953)

R.H. Thomlinson et al.

The histological structure of some human lung cancers and the possible implications for radiotherapy

Br J Cancer

(1955)

W.E. Powers et al.

A multicomponent x-ray survival curve for mouse lymphosarcoma cells irradiated in vivo

Nature

(1963)

Elkind MM, Swain RW, Alescio T, et al. Oxygen, nitrogen, recovery and radiation therapy. In: University of Texas, M.D....

J.S. Bedford et al.

The effect of hypoxia and radiation response of mammalian cells in culture

Br J Radiol

(1974)

T.G. Graeber et al.

Hypoxia-mediated cells with diminished apoptotic potential in solid tumours

Nature

(1996)

T.Y. Reynolds et al.

Genetic instability induced by the tumor microenvironment

Cancer Res

(1996)

M.C. Höckel et al.

Intratumoral Po₂ predicts survival in advanced cancer of the uterine cervix

Radiother Oncol

(1993)

M.C. Höckel et al.

Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix

Cancer Res

(1996)

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After the 60 mmHg of pressure of O2, the OER values have a trend to value constant. Figs. 3 and 4 confirm the increasing of the deposited energy for tumors with high concentration of oxygen, due the oxygen effect that is disregarded in accuracy of the ionization radiation treatment (Kirkpatrick et al., 2004; Ye, 1999). The dose distributions shown in Fig. 5 visually show almost the same distribution, but when the field profile of both distributions, shown in Fig. 6, a difference of 7.29% was found at a radial distance of 0.6 mm of the tumor.
Cells with normal oxygenation are more sensitive to the effects of ionizing radiation than those with hypoxic conditions, because O₂ molecules react rapidly with free radicals, produced by irradiation, originating highly reactive radicals. Thus, the different concentrations of hypoxia in tumors can modulate the response of the irradiation through the radioresistance they present. The objective of this work is to study the dose distributions in cranial tumors with hypoxia through the simulation of the PENELOPE-Monte Carlo code, simulating a cranial tumor with various concentrations of oxygen. The obtained results were evaluated in terms of oxygen enhancement ratio (OER), energy deposited and beam profiles of the dose distributions of the tumors with different concentrations of oxygen. From the simulation data, it was shown that the code is able to evidence the effect of oxygen in dose distribution. A maximum difference of 7.29% were found when compared values of tumor with different concentrations of oxygen and with normal oxygenation conditions. We can assume that PENELOPE can be simulated the dose response of the tumors with different concentrations of oxygen, proving that, its oxygen concentration modulates the treatment response and carrying with it the risk of survival of the treated tumor cells.
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Radiosensitivity of mammalian cells increases sharply from 0 to 10 mmHg with the half-maximum radiosensitivity at approximately pO2 = 3 mmHg [24,25]. At or above the physiological range of pO2 (>30 mmHg), mammalian cells are close to being fully sensitized by molecular oxygen to ionizing radiation [6,23]. Therefore, the radiobiological hypoxia where mammalian cells are the most radioresistant occurs primarily in the range of pO2 < 3 mmHg or 0.4% O2 [7].
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However, individual cell cycle phase distributions have been recently incorporated to enable phase-specific radiosensitivity assignment (Fig. 1). Further, Gaussian shaped pO2 histograms (Fig. 2) are now utilized for cell oxygenation assignment, which are converted to oxygen enhancement ratio (OER) values for the purposes of cell death probability calculations during radiation therapy, with pO2 (0.1-100.0 mm Hg) to OER conversion (1.2-3.1) via a continuous function (19). Total cell number thresholds were embedded into the algorithm to alter the applied Gaussian pO2 distribution according to current tumor cell number (ie, volume), representing 4 different stages of deoxygenation (or reoxygenation) during tumor growth or shrinkage (Fig. 2).
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^☆: Supported in part by NIH/NCI grant CA40355.

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Biology contributionPredicting the effect of temporal variations in po2 on tumor radiosensitivity☆

Abstract

Purpose

Methods and materials

Results

Conclusion

Introduction

Section snippets

Tumor oxygenation measurement

Results

Discussion

Conclusion

Acknowledgements

Semin Radiat Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Semin Radiat Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy

Br J Radiol

The histological structure of some human lung cancers and the possible implications for radiotherapy

Br J Cancer

A multicomponent x-ray survival curve for mouse lymphosarcoma cells irradiated in vivo

Nature

The effect of hypoxia and radiation response of mammalian cells in culture

Br J Radiol

Hypoxia-mediated cells with diminished apoptotic potential in solid tumours

Nature

Genetic instability induced by the tumor microenvironment

Cancer Res

Intratumoral Po2 predicts survival in advanced cancer of the uterine cervix

Radiother Oncol

Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix

Cancer Res

Biology contribution
Predicting the effect of temporal variations in po₂ on tumor radiosensitivity☆

Intratumoral Po₂ predicts survival in advanced cancer of the uterine cervix