Radiotherapy for Non-Small Cell Lung Cancer Induces DNA Damage Response in Both Irradiated and Out-of-field Normal Tissues.
OBJECTIVE
To study the response of irradiated and out-of-field normal tissues during localized curative intent radiotherapy.


METHODS
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. Clin Cancer Res; 22(19); 4817-26. ©2016 AACRSee related commentary by Verma and Lin, p. 4763.
Sir 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.
Shankar
S
Siva
Sir 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.
Pavel
P
Lobachevsky
Sir 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.
Michael P
MP
MacManus
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. Department of Physical Sciences, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Tomas
T
Kron
Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Andreas
A
Möller
Tumour Microenvironment Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Richard J
RJ
Lobb
Molecular Radiation Biology Laboratory, Cancer Cell Biology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Jessica
J
Ventura
Molecular Radiation Biology Laboratory, Cancer Cell Biology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Nickala
N
Best
Molecular Radiation Biology Laboratory, Cancer Cell Biology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
Jai
J
Smith
Sir 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.
David
D
Ball
Sir 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.
Olga A
OA
Martin
D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000532:radiotherapy*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000532:radiotherapy*; D008214:Lymphocytes / Q000528:radiation effects; D008297:Male; D008875:Middle Aged; D011832:Radiation Injuries; D020266:Radiotherapy, Conformal / Q000009:adverse effects*