Radiation responses of cancer and normal cells to split dose fractions with uniform and grid fields: increasing the therapeutic ratio

Abstract

Purpose

Radiation treatment of cancer is usually delivered in a prescribed sequence of dose fractions within which the dependence of dose on time is determined by the treatment plan. New techniques, such as stereotactic body radiation therapy (SBRT) and image guided radiation therapy (IGRT) have been introduced with the motivation of improving therapeutic outcomes, with the consequence that the time dependence of the dose within a fraction is modified. Here, we test whether an increased toxicity to cancer cells arises when a radiation treatment fraction is delivered in two equal parts, allowing time for the expression of factors, for example, RONS and cytokines, in response to the first dose which may sensitize cells to the second dose. A medium time delay between 15 and 60 minutes is proposed to allow factors to be expressed before repair takes place. A grid field is used to enhance diffusion of the factors.

Materials and methods

The cell lines used in the study were two prostate cancers (LNCaP and DU 145), a normal prostate (PNT1A), a non-small cell lung cancer (NCI-H460), and a glioma (Hs 683). Uniform or spatially modulated grid fields, delivering the same mean dose, were used. The results for the clonogenic survival fractions were grouped into a ‘short’ delay (under 10 minutes) and a ‘medium’ delay (between 15 and 60 minutes).

Results

The medium delay with a grid field yielded a significant increase in toxicity for the four cancer cell lines. The medium delay with a uniform field gave a significant increase in toxicity for the two prostate cancer cell lines. A highly significant increase was found in the therapeutic ratio, defined as the ratio of the survival of prostate normal to prostate cancer cells.

Conclusions

The findings show that the intra-fractional dose schedule with medium time delay offers an opportunity to increase the toxicity of radiation to cancer cells, relative to a single radiation delivery. For all cancer cell lines, a grid field gives a greater toxic effect than a uniform field. The split dose treatment offers an increase in cancer toxicity while preserving normal cells, improving the outcomes of a treatment.

Keywords:

• Split dose
• bystander effect
• spatial modulation
• grid field
• therapeutic ratio
• clonogenic assay

Acknowledgements

We wish to acknowledge Kim Rogers, VR Shop for Figure 4 and Stephen Bathgate for Figure 4B.

Author contributions

All authors contributed to the study conception and design. Experiments were carried out by Linda Rogers and Natalka Suchowerska. Data analysis and statistical analysis were performed by Linda Rogers and David McKenzie. The Supplementary data showing the presence of hydrogen peroxide in irradiated solution was carried out by Juliette Harley. All authors have contributed to the writing of the manuscript and have approved the final version.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors wish to thank Ian and Margaret Bailey for funding this project.

Notes on contributors

Linda Joanne Rogers

Linda Joanne Rogers, BMedSci is the Radiobiology Laboratory Manager and Cell Biologist in the department of Radiation Oncology at Chris O’Brien Lifehouse, Sydney, Australia.

Juliette Cornelia Harley

Linda Joanne Rogers, BMedSci is the Radiobiology Laboratory Manager and Cell Biologist in the department of Radiation Oncology at Chris O’Brien Lifehouse, Sydney, Australia.

Juliette Cornelia Harley is a PhD student with the School of Physics, University of Sydney, Australia.

David Robert McKenzie

David Robert McKenzie, PhD FAIP is a Professor in Materials Physics in the School of Physics, Co-director of VectorLAB, University of Sydney, Australia and the Department of Radiation Oncology at Chris O’Brien Lifehouse, Australia.

Natalka Suchowerska

Natalka Suchowerska, PhD FACPSEM, Medical Physicist, is an Associate Professor in the School of Physics, Co-director of VectorLAB, University of Sydney, Australia.