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Nondosimetric risk factors for radiation-induced lung toxicity.

ABSTRACT: The decision to administer a radical course of radiotherapy (RT) is largely influenced by the dose-volume metrics of the treatment plan, but what are the patient-related and other factors that may independently increase the risk of radiation lung toxicity? Poor pulmonary function has been regarded as a risk factor and a relative contraindication for patients undergoing radical RT, but recent evidence suggests that patients with poor spirometry results may tolerate conventional or high-dose RT as well as, if not better than, patients with normal function. However, caution may need to be exercised in patients with underlying interstitial pulmonary fibrosis. Furthermore, there is emerging evidence of molecular markers of increased risk of toxicity. This review discusses patient-related risk factors other than dosimetry for radiation lung toxicity.

SUBMITTER: Kong FM

PROVIDER: S-EPMC4400801 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Nondosimetric risk factors for radiation-induced lung toxicity.

Kong Feng-Ming Spring FM Wang Shulian S

Seminars in radiation oncology 20141215 2

The decision to administer a radical course of radiotherapy (RT) is largely influenced by the dose-volume metrics of the treatment plan, but what are the patient-related and other factors that may independently increase the risk of radiation lung toxicity? Poor pulmonary function has been regarded as a risk factor and a relative contraindication for patients undergoing radical RT, but recent evidence suggests that patients with poor spirometry results may tolerate conventional or high-dose RT as ...[more]

PMID: 25771414

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Project description:PurposeDose to normal lung has commonly been linked with radiation-induced lung toxicity (RILT) risk, but incorporating functional lung metrics in treatment planning may help further optimize dose delivery and reduce RILT incidence. The purpose of this study was to investigate the impact of the dose delivered to functional lung regions by analyzing perfusion (Q), ventilation (V), and combined V/Q single-photon-emission computed tomography (SPECT) dose-function metrics with regard to RILT risk in patients with non-small cell lung cancer (NSCLC) patients who received radiation therapy (RT).Methods and materialsSPECT images acquired from 88 patients with locally advanced NSCLC before undergoing conventionally fractionated RT were retrospectively analyzed. Dose was converted to the nominal dose equivalent per 2 Gy fraction, and SPECT intensities were normalized. Regional lung segments were defined, and the average dose delivered to each lung region was quantified. Three functional categorizations were defined to represent low-, normal-, and high-functioning lungs. The percent of functional lung category receiving ≥20 Gy and mean functional intensity receiving ≥20 Gy (iV20) were calculated. RILT was defined as grade 2+ radiation pneumonitis and/or clinical radiation fibrosis. A logistic regression was used to evaluate the association between dose-function metrics and risk of RILT.ResultsBy analyzing V/Q normalized intensities and functional distributions across the population, a wide range in functional capability (especially in the ipsilateral lung) was observed in patients with NSCLC before RT. Through multivariable regression models, global lung average dose to the lower lung was found to be significantly associated with RILT, and Q and V iV20 were correlated with RILT when using ipsilateral lung metrics. Through a receiver operating characteristic analysis, combined V/Q low-function receiving ≥20 Gy (low-functioning V/Q20) in the ipsilateral lung was found to be the best predictor (area under the curce: 0.79) of RILT risk.ConclusionsIrradiation of the inferior lung appears to be a locational sensitivity for RILT risk. The multivariable correlation between ipsilateral lung iV20 and RILT, as well as the association of low-functioning V/Q20 and RILT, suggest that irradiating low-functioning regions in the lung may lead to higher toxicity rates.

Project description:Background: To investigate the role of stereotactic body RT (SBRT) in decreased total peripheral lymphocyte count (TLC) in patients with early-stage lung cancer and to explore possible risk factors for RT-induced lymphopenia. Materials and Methods: We analyzed the TLCs and lymphocyte subsets of 76 patients in our prospective clinical database who received SBRT for early-stage lung cancer treatment. Relationships between clinical factors or dosimetric parameters and TLC were evaluated using Spearman's correlation analysis and Chi-square tests for continuous and categorical variables, respectively. Multivariate linear regression analysis was used to control for confounding factors. Kaplan-Meier analysis with a log-rank test and a multivariate Cox regression model were used for survival analysis. Results: Most patients (64/76, 84.2%) experienced decreased absolute lymphocyte counts following SBRT, as well as shifts in lymphocyte subset distributions. Spearman's correlation coefficients between post-SBRT TLC and the percentage of the lung and heart receiving 5 to 50 Gy (in 5 Gy increments) shown that most lung DVH parameters [V(10)-V(50)] were significantly negatively correlated with post-SBRT TLC, while only heart V(5), V(20), V(25), V(30), and V(45) were significant. Univariate analyses revealed that a lower Pre-SBRT TLC level, higher mean lung dose, longer treatment duration, and longer TBT were significantly associated with a lower Post-SBRT TLC level (all P < 0.05). Stepwise multivariate linear regression, which incorporated all of the significantly clinical variables and SBRT-related parameters in univariate analysis, revealed that lower pre -SBRT TLC (P < 0.001), higher heart V5 (P = 0.002), and longer total beam-on time (TBT) (P = 0.001) were the independent risk factors for decrease in post-SBRT TLC. Patients with lower post-SBRT TLC and longer TBT exhibited significantly inferior progression-free survival (PFS) (P < 0.001 and P = 0.013) and overall survival (P = 0.006 and P = 0.043). Conclusions: G2 and more severe lymphopenia after SBRT might be an independent prognostic factor for poorer outcome in early-stage lung cancer. Lowering heart V5 and TBT when designing SBRT plans may spare circulating lymphocytes and have the potential to further improve survival outcomes.

Project description:Human stem cell-derived extracellular vesicles (EV) provide many advantages over cell-based therapies for the treatment of functionally compromised tissue beds and organ sites. Here we sought to determine whether human embryonic stem cell (hESC)-derived EV could resolve in part, the adverse late normal tissue complications associated with exposure of the lung to ionizing radiation. The hESC-derived EV were systemically administered to the mice via the retro-orbital sinus to explore the potential therapeutic benefits following exposure to high thoracic doses of radiation (14 Gy). Data demonstrated that hESC-derived EV treatment significantly improved overall survival of the irradiated cohorts (P < 0.001). Increased survival was also associated with significant reductions in lung fibrosis as quantified by CBCT imaging (P < 0.01, 2 weeks post-irradiation). Qualitative histological analyses revealed reduced indications of radiation induced pulmonary injury in animals treated with EV. EV were then subjected to a rigorous proteomic analysis to ascertain the potential bioactive cargo that may prove beneficial in ameliorating radiation-induced normal tissue toxicities in the lung. Proteomics validated several consensus exosome markers (e.g., CD68) and identified major classes of proteins involved in nuclear pore complexes, epigenetics, cell cycle, growth and proliferation, DNA repair, antioxidant function, and cellular metabolism (TCA cycle and oxidative phosphorylation, OXYPHOS). Interestingly, EV were also found to contain mitochondrial components (mtDNA, OXYPHOS protein subunits), which may contribute to the metabolic reprograming and recovery of radiation-injured pulmonary tissue. To evaluate the safety of EV treatments in the context of the radiotherapeutic management of tumors, mice harboring TC1 tumor xenografts were subjected to the same EV treatments shown to forestall lung fibrosis. Data indicated that over the course of one month, no change in the growth of flank tumors between treated and control cohorts was observed. In conclusion, present findings demonstrate that systemic delivery of hESC-derived EV could ameliorate radiation-induced normal tissue complications in the lung, through a variety of potential mechanisms based on EV cargo analysis.

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Nondosimetric risk factors for radiation-induced lung toxicity.

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Nondosimetric risk factors for radiation-induced lung toxicity.

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