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

doi:10.1016/j.ijrobp.2016.03.024

International Journal of Radiation OncologyBiologyPhysics

Volume 95, Issue 5, 1 August 2016, Pages 1357-1366

Presented in part as an oral presentation at the 56th Annual Meeting of the American Society for Radiation Oncology, San Francisco, CA, Sept 14-17, 2014.

https://doi.org/10.1016/j.ijrobp.2016.03.024 Get rights and content

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.

Introduction

Stereotactic body radiation therapy (SBRT) is the standard of care for patients with medically inoperable stage I non–small cell lung cancer (NSCLC) (1). For operable patients with early-stage NSCLC, a meta-analysis (2) of 11,921 patients in 63 studies demonstrated that overall survival or disease-free survival did not differ significantly between SBRT and surgery when patients' baseline condition was comparable. Recent studies 3, 4, 5, 6, 7, 8 have demonstrated effectiveness of SBRT for oligometastasis(es) (1-5 pulmonary nodules).

Radiation-induced lung toxicities (RILT), including radiation pneumonitis (RP) and clinical lung fibrosis, are important dose-limiting toxicities. From published data to date, the rate of symptomatic RP ranged from 0% to 49% 9, 10, 11, 12; the rate of radiation-induced lung fibrosis, which can continue to evolve beyond 1 year after SBRT, is reportedly up to 70% to 80% in high-dose regions (13), albeit most often asymptomatic. Fatal (grade 5) RILT after SBRT warrants serious consideration although it is only sporadically reported (14).

Many factors, including patient-related, tumor-related, and dosimetric factors, may play important roles in the risk of RILT (15). SBRT dose and fractionation are often considered important, affecting clinical management decisions with respect to lung tolerance and tumor control, particularly in elderly patients, those with chronic lung interstitial diseases, or both 12, 16. Physical dosimetric measures such as mean lung dose (MLD) and lung V20 (percent or absolute volume receiving over 20 Gy), often used to guide clinical practice, were analyzed in some studies, showing inconsistent relationship with RILT after SBRT 17, 18, 19, perhaps because of the limited number of toxicity events from each study.

Here we aimed to examine the risk of RILT after thoracic SBRT from the published studies to date and to study the significance of clinical and simple dosimetric risk factors in relation to RILT.

Section snippets

Selection criteria

Eligible studies included those that described treatment with SBRT for either primary NSCLC or metastatic lung tumors. Detailed reporting of RILT, including rate and grade, after SBRT was required. Studies of patients who received radiation therapy before SBRT, SBRT in conjunction with systemic therapy, SBRT as a boost therapy after conventional radiation therapy, or a combination of these were excluded. Publications were limited to those written in English.

Search methods

Studies published before December

Patients and study characteristics

A total of 329 studies were identified at the initial search, including all studies of SBRT for lung tumors; 241 studies were excluded because of (1) RILT data missing; (2) duplications of publications or publications with overlapping data; (3) prior thoracic radiation treatments with or without concurrent chemotherapy; or (4) nonoriginal publications such as meta-analyses, reviews, or case reports. Eighty-eight original studies including 7752 patients were eligible for this analysis. Figure 1

Discussion

This was a pooled analysis of 88 published studies (7752 patients) for lung toxicity and risk assessment after lung SBRT. The overall estimated rate of 9.1% for G2+ RILT was acceptably low. Older age, larger tumor, stage IB (vs IA) NSCLC, MLD, and V20 were significant factors for higher risk of symptomatic toxicity, whereas gender, prescription dose, and dose fractionation were not. To our knowledge, this is the first pooled analysis of lung toxicities after lung SBRT.

Although the pooled rate

Acknowledgment

The authors thank the experts of AAPM SBRT Thoracic NTCP working group for their valuable discussions and comments.

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: Supported in part by NIH/NCI R01 CA142840 (PI: F.-M. Kong), in preparation for a research grant of SBRT from Varian Medical Systems.

: Conflict of interest: none.

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

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Selection criteria

Search methods

Patients and study characteristics

Discussion

Acknowledgment

Int J Radiat Oncol Biol Phys

Lancet Oncol

Lancet Oncol

Int J Radiat Oncol Biol Phys

J Thorac Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Lung Cancer

Radiat Oncol

Int J Radiat Oncol Biol Phys

Lung Cancer

Radiother Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

J Thorac Oncol

Chest

Int J Radiat Oncol Biol Phys

J Thorac Oncol

Radiat Oncol

Pract Radiat Oncol

Int J Radiat Oncol Biol Phys

Radiat Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Radiother Oncol

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