^{1,a)}, Nagaraju Mogili

^{1}, Brian Marples

^{1,b)}and Jay Burmeister

^{1}

### Abstract

**Purpose:**

To experimentally simulate IMRT delivery using two human cell models*in vitro* and test the hypothesis that a loss in effective dose resulting from the prolongation of megavoltage x-raytreatment delivery time would be greatly reduced in corresponding IMRT simulations using higher-LET radiation.

**Methods:**

The effect of prolonging the delivery time of a treatment fraction was investigated*in vitro* using human PC-3 prostate and HGL21 glioblastoma tumorcell lines. Cells were irradiated with x rays from a conventional linear accelerator or with neutrons from a clinical radiotherapy beam and maintained at throughout. The delivery time for six closely spaced doses, simulating six multiple-port segments, was varied from acute to 60 min for x-rayirradiation, and acute to 120 min for neutron irradiation.Cell survival was measured following summed doses for the six segments of 0.5–6 Gy for x rays and 0.16–2 Gy for neutrons, covering the most likely range of dose per fraction used in clinical radiotherapy.

**Results:**

Prolonging x-ray delivery time (from initiation of segment 1 to initiation of segment 6) from 5 to 45 min resulted in a loss in effective total dose (in equivalent 2 Gy multifraction treatments) of 5.6% in the PC-3 cell line and 11.7% in the HGL21 cell line. More clinically common prolongations of 5–30 and 5–15 min resulted in effective dose reductions of 3.8% and 1.7% for PC-3, and 7.3% and 2.9% for HGL21. A loss of less than 0.5% in effective dose was observed for prolongations up to 45 min of similarly effective neutron irradiation of PC-3 and HGL21 cells.

**Conclusions:**

Prolonged delivery times of photon fractions could have a significant impact on treatment outcome especially for tumors with a low ratio and short repair halftime. These effects are significant at delivery times commonly associated with IMRT and are variable with cell type. X-rayIMRT should therefore always be planned to minimize dose-fraction delivery time. However, if IMRTtreatments are delivered with high-LET radiation, this considerably reduces the dependence of the biological effect on fraction delivery time even out to 2 h.

This work was partly supported by funds from the Wayne State University Medical Physics Graduate Program and by the Department of Radiation Oncology, Wayne State University Medical School.

I. INTRODUCTION

II. METHODS AND MATERIALS

II.A. Cell lines and culture

II.B. Irradiations

II.C. Experimental design

II.D. Assay of radiationeffect

III. RESULTS

IV. DISCUSSION

V. CONCLUSIONS

### Key Topics

- Dosimetry
- 91.0
- Neutrons
- 38.0
- Intensity modulated radiation therapy
- 27.0
- Cancer
- 25.0
- X-ray effects
- 24.0

## Figures

Cell survival versus dose data for PC-3 cells exposed to x rays (panel a) and neutrons (panel b) at the different durations of overall delivery time of all the six subfractions: 0–60 min for x rays and 0–120 min for neutrons. The time-dependent variability in the x-ray response is substantially reduced in the neutron response, at similar levels of surviving fraction. Panel c (x rays) and panel d (neutrons) present these same data as surviving fraction versus time for each total dose delivered.

Cell survival versus dose data for PC-3 cells exposed to x rays (panel a) and neutrons (panel b) at the different durations of overall delivery time of all the six subfractions: 0–60 min for x rays and 0–120 min for neutrons. The time-dependent variability in the x-ray response is substantially reduced in the neutron response, at similar levels of surviving fraction. Panel c (x rays) and panel d (neutrons) present these same data as surviving fraction versus time for each total dose delivered.

Cell survival versus dose data for HGL21 cells exposed to x rays (panel a) and neutrons (panel b) at the different durations of overall delivery time of all the six subfractions: 0–60 min for x rays and 0–120 min for neutrons. The time-dependent variability in the x-ray response is reduced in the neutron response, at similar levels of surviving fraction. Panel c (x rays) and panel d (neutrons) present these same data as surviving fraction versus time for each total dose delivered.

Cell survival versus dose data for HGL21 cells exposed to x rays (panel a) and neutrons (panel b) at the different durations of overall delivery time of all the six subfractions: 0–60 min for x rays and 0–120 min for neutrons. The time-dependent variability in the x-ray response is reduced in the neutron response, at similar levels of surviving fraction. Panel c (x rays) and panel d (neutrons) present these same data as surviving fraction versus time for each total dose delivered.

Predicted responses calculated from the parameter values in Table I, of PC-3 cells to the six-segment irradiation with either x rays (panels a and c) or neutrons (panels b and d), as a function of either dose (panels a and b) or overall irradiation time (panels c and d). These diagrams show the loss of effectiveness of at least 5% dose equivalent as the six-segment x-ray irradiation is protracted beyond 30 min duration, and that this loss is reduced substantially by utilizing high-LET irradiation.

Predicted responses calculated from the parameter values in Table I, of PC-3 cells to the six-segment irradiation with either x rays (panels a and c) or neutrons (panels b and d), as a function of either dose (panels a and b) or overall irradiation time (panels c and d). These diagrams show the loss of effectiveness of at least 5% dose equivalent as the six-segment x-ray irradiation is protracted beyond 30 min duration, and that this loss is reduced substantially by utilizing high-LET irradiation.

Predicted responses calculated from the parameter values in Table I, of HGL21 cells to the six-segment irradiation with either x rays (panels a and c) or neutrons (panels b and d), as a function of either dose (panels a and b) or overall irradiation time (panels c and d). These diagrams show the loss of effectiveness of at least 5% dose equivalent as the six-segment x-ray irradiation is protracted beyond 30 min duration, and that this loss is reduced substantially by utilizing high-LET irradiation.

Predicted responses calculated from the parameter values in Table I, of HGL21 cells to the six-segment irradiation with either x rays (panels a and c) or neutrons (panels b and d), as a function of either dose (panels a and b) or overall irradiation time (panels c and d). These diagrams show the loss of effectiveness of at least 5% dose equivalent as the six-segment x-ray irradiation is protracted beyond 30 min duration, and that this loss is reduced substantially by utilizing high-LET irradiation.

Increase in surviving fraction of PC-3 (panel a) and HGL21 (panel b) cells for a 2 Gy x-ray dose protracted out to 1 h and a similarly effective neutron dose extended out to 2 h, calculated from the parameters in Table I. The neutron responses demonstrate a considerably lessened effect of dose protraction compared with the x-ray responses.

Increase in surviving fraction of PC-3 (panel a) and HGL21 (panel b) cells for a 2 Gy x-ray dose protracted out to 1 h and a similarly effective neutron dose extended out to 2 h, calculated from the parameters in Table I. The neutron responses demonstrate a considerably lessened effect of dose protraction compared with the x-ray responses.

## Tables

Parameters in the incomplete-repair model fitted separately to the x-ray data and neutron data for each cell line. 95% confidence intervals are shown in parentheses. Note that although values for neutrons are given which minimize the sum of squared errors in the nonlinear regression, these values are technically indeterminate as indicated by their infinite confidence intervals.

Parameters in the incomplete-repair model fitted separately to the x-ray data and neutron data for each cell line. 95% confidence intervals are shown in parentheses. Note that although values for neutrons are given which minimize the sum of squared errors in the nonlinear regression, these values are technically indeterminate as indicated by their infinite confidence intervals.

Parameters in the incomplete-repair model fitted to all the data (x ray and neutron simultaneously) for each cell line. 95% confidence intervals are shown in parentheses.

Parameters in the incomplete-repair model fitted to all the data (x ray and neutron simultaneously) for each cell line. 95% confidence intervals are shown in parentheses.

Percent increase in the isoeffective dose per fraction, caused by example treatment protractions, calculated using the parameters in the incomplete-repair model fitted separately to the x-ray data and neutron data for each human cell line (see Table I). This analysis assumes that the number of fractions would be kept constant, and the fraction size would be increased to compensate for loss of effectiveness. Normal type: X rays; italic type: Neutrons.

Percent increase in the isoeffective dose per fraction, caused by example treatment protractions, calculated using the parameters in the incomplete-repair model fitted separately to the x-ray data and neutron data for each human cell line (see Table I). This analysis assumes that the number of fractions would be kept constant, and the fraction size would be increased to compensate for loss of effectiveness. Normal type: X rays; italic type: Neutrons.

Percent increase in the isoeffective total dose (given in multiple equal fractions) caused by example treatment protractions, calculated using parameters in the incomplete-repair model fitted separately to the x-ray data and neutron data for each human cell line (see Table I). This analysis assumes that the fraction size would be kept constant and the number of fractions would be increased to compensate for loss of effectiveness. Normal type: X rays; italic type: Neutrons.

Percent increase in the isoeffective total dose (given in multiple equal fractions) caused by example treatment protractions, calculated using parameters in the incomplete-repair model fitted separately to the x-ray data and neutron data for each human cell line (see Table I). This analysis assumes that the fraction size would be kept constant and the number of fractions would be increased to compensate for loss of effectiveness. Normal type: X rays; italic type: Neutrons.

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