Survival from non-small cell lung cancer (NSCLC) is poor with dose intensification limited by risks of radiation injury to the heart and lungs. We present our work on evaluating predictors of individual radiation response and discuss our plan to further assess this in a prospective clinical trial.
A prospective observational trial (majority of patients received 60 Gy in 30 fractions) was conducted involving 87 non-small cell lung cancer patients who underwent functional lung imaging (V/Q PET) before, during and after treatment.(1) In parallel, blood samples and eyebrow hair follicles were collected. The γ-H2AX assay was used to monitor DNA damage in peripheral blood lymphocytes and hairs. Pro-inflammatory cytokine concentrations were measured in plasma.
There was a strong correlation decrease in perfusion, density and ventilation with radiation dose (all r2 > 0.95, all p < 0.01).(2) The γ-H2AX response correlated to dose delivered to lung in circulating lymphocytes (r=0.739 p=0.009) but not in out of field hair follicles (r=0.684 p=0.062).(3) Plasma cytokine concentrations (IP-10, IL-6, MCP-1, TIMP-1, Eotaxin) were statistically significant predictors of clinical toxicity.(4) Non-linear regression analysis of DNA damage repair kinetics in a subset of 11 patients demonstrated improved DNA damage repair efficiency during and after radiotherapy.
We now have a methodology to identify patients at risk of radiotherapy toxicity and decreased treatment response, however it needs further validation. A prospective interventional trial with 20 patients opens in 2018, which involves adapting radiotherapy plans to avoid functional lung toxicity identified on V/Q PET with dose escalation to the primary site (69 Gy in 30 fractions). Primary outcome is the rate of radiation pneumonitis. In addition, the radiobiological biomarker study will be extended. Plasma cytokine concentrations will be correlated with radiation-induced pneumonitis; DNA damage and repair pathway(s) and factors involved in the radiation treatment response will be identified.