Simple Factors Associated With Radiation-Induced Lung Toxicity After Stereotactic Body Radiation Therapy of the Thorax: A Pooled Analysis of 88 Studies

Abstract

Purpose: To study the risk factors for radiation-induced lung toxicity (RILT) after stereotactic body radiation therapy (SBRT) of the thorax.

Methods and materials: Published studies on lung toxicity in patients with early-stage non-small cell lung cancer (NSCLC) or metastatic lung tumors treated with SBRT were pooled and analyzed. The primary endpoint was RILT, including pneumonitis and fibrosis. Data of RILT and risk factors were extracted from each study, and rates of grade 2 to 5 (G2+) and grade 3 to 5 (G3+) RILT were computed. Patient, tumor, and dosimetric factors were analyzed for their correlation with RILT.

Results: Eighty-eight studies (7752 patients) that reported RILT incidence were eligible. The pooled rates of G2+ and G3+ RILT from all 88 studies were 9.1% (95% confidence interval [CI]: 7.15-11.4) and 1.8% (95% CI: 1.3-2.5), respectively. The median of median tumor sizes was 2.3 (range, 1.4-4.1) cm. Among the factors analyzed, older patient age (P=.044) and larger tumor size (the greatest diameter) were significantly correlated with higher rates of G2+ (P=.049) and G3+ RILT (P=.001). Patients with stage IA versus stage IB NSCLC had significantly lower risks of G2+ RILT (8.3% vs 17.1%, odds ratio = 0.43, 95% CI: 0.29-0.64, P<.0001). Among studies that provided detailed dosimetric data, the pooled analysis demonstrated a significantly higher mean lung dose (MLD) (P=.027) and V20 (P=.019) in patients with G2+ RILT than in those with grade 0 to 1 RILT.

Conclusions: The overall rate of RILT is relatively low after thoracic SBRT. Older age and larger tumor size are significant adverse risk factors for RILT. Lung dosimetry, specifically lung V20 and MLD, also significantly affect RILT risk.

Fig. 1. Study selection schema

Fig. 2. RILT after SBRT

Plots show mean rates of RILT in all patients (A), primary and metastatic diseases separately (B-C), RP (D) and lung fibrosis (E). The number of patients differs from plot to plot, and point to point based on availability of such data. The comparison of RILT rates for primary and metastatic lung tumors are also shown and for G2+ (B) and G3+ RILT (C), when the horizontal bars show the Mean±95%CI values of RILT rate in each subgroup (B and C). SBRT= Stereotactic body radiation therapy, RILT = radiation induced lung toxicity, RP = radiation pneumonitis. RILT includes both RP and fibrosis.

Fig. 3. Patient/tumor factors and RILT

Linear regression analysis were performed for all continuous variables. Representative plots are shown. RILT= radiation induced lung toxicity. G2+= grade 2 and above, G3+= grade 3 and above. Plotted and analyzed data included only studies with relevant information provided. The error bars show the range of the data. A: Age and G2+ RILT (P= 0.045). B: Tumor size (the largest dimension) and G2+ RILT (P= 0.049). C: Tumor size (the largest dimension) and G3+ RILT (P= 0.001). D. Tumor location and G2+ RILT (P= 0.13). E. Median GTV with G2+ RILT (P= 0.11). F: Median PTV with G2+ RILT (P= 0.21). G: Forest plot for RILT between male and female (P= 0.44). H: Forest plot for RILT between different tumor locations (centrally vs peripherally located) (P= 0.65). I: Forest plot for RILT between stage IA and IB (P< 0.001).

Fig. 4. Dosimetric factors and RILT

This figure shows G2+ RILT rates versus BED10 (A), whole lung MLD (B) and V20 (C) of individual studies, and dosimetric comparisons between G2+RILT of limited studies provided detailed breakdown dosimetric data: MLD of the whole lung (D), MLD of ipsilateral lung (E), and V20 (F). BED10=biologically effective dose of using alpha/beta of 10. MLD= Mean Lung Dose; V20= volume at and above 20 Gy; RILT= radiation induced lung toxicity.