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Abstract

PURPOSE:

To study the response of irradiated and out-of-field normal tissues during localized curative intent radiotherapy.

EXPERIMENTAL DESIGN:

Sixteen patients with non-small cell lung carcinoma (NSCLC) received 60 Gy in 30 fractions of definitive thoracic radiotherapy with or without concurrent chemotherapy. Peripheral blood lymphocytes (PBL) and eyebrow hairs were sampled prior, during, and after radiotherapy. Clinical variables of radiotherapy dose/volume, patient age, and use of chemoradiotherapy were tested for association with γ-H2AX foci, a biomarker of DNA damage that underlies cellular response to irradiation.

RESULTS:

Radiotherapy induced an elevation of γ-H2AX foci in PBL, representing normal tissues in the irradiated volume, 1 hour after fraction one. The changes correlated directly with mean lung dose and inversely with age. γ-H2AX foci numbers returned to near baseline values in 24 hours and were not significantly different from controls at 4 weeks during radiotherapy or 12 weeks after treatment completion. In contrast, unirradiated hair follicles, a surrogate model for out-of-field normal tissues, exhibited delayed "abscopal" DNA damage response. γ-H2AX foci significantly increased at 24 hours post-fraction one and remained elevated during treatment, in a dose-independent manner. This observed abscopal effect was associated with changes in plasma levels of MDC/CCL22 and MIP-1α/CCL3 cytokines. No concordant changes in size and concentration of circulating plasma exosomes were observed.

CONCLUSIONS:

Both localized thoracic radiotherapy and chemoradiotherapy induce pronounced systemic DNA damage in normal tissues. Individual assessment of biologic response to dose delivered during radiotherapy may allow for therapeutic personalization for patients with NSCLC.

Author information​

Siva S1, Lobachevsky P2, MacManus MP3, Kron T4, Möller A5, Lobb RJ5, Ventura J6, Best N6, Smith J6, Ball D3, Martin OA7.

1Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. shankar.siva@petermac.org.

2Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. Molecular Radiation Biology Laboratory, Cancer Cell Biology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.

3Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.

4Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. Department of Physical Sciences, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.

5Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

6Molecular Radiation Biology Laboratory, Cancer Cell Biology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.

7Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. Division of Radiation Oncology and Cancer Imaging, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia. Molecular Radiation Biology Laboratory, Cancer Cell Biology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.