Clinical Investigation
Lack of a Dose-Effect Relationship for Pulmonary Function Changes After Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer

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Purpose

To evaluate the influence of tumor size, prescription dose, and dose to the lungs on posttreatment pulmonary function test (PFT) changes after stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC).

Methods and Materials

The analysis is based on 191 patients treated at 5 international institutions: inclusion criteria were availability of pre- and post-SBRT PFTs and dose-volume histograms of the lung and planning target volume (PTV); patients treated with more than 1 SBRT course were excluded. Correlation between early (1-6 months, median 3 months) and late (7-24 months, median 12 months) PFT changes and tumor size, planning target volume (PTV) dose, and lung doses was assessed using linear regression analysis, receiver operating characteristics analysis, and Lyman's normal tissue complication probability model. The PTV doses were converted to biologically effective doses and lung doses to 2 Gy equivalent doses before correlation analyses.

Results

Up to 6 months after SBRT, forced expiratory volume in 1 second and carbon monoxide diffusion capacity changed by −1.4% (95% confidence interval [CI], −3.4% to 0) and −7.6% (95% CI, −10.2% to −3.4%) compared with pretreatment values, respectively. A modest decrease in PFTs was observed 7-24 months after SBRT, with changes of −8.1% (95% CI, −13.3% to −5.3%) and −12.4% (95% CI, −15.5% to −6.9%), respectively. Using linear regression analysis, receiver operating characteristic analysis, and normal tissue complication probability modeling, all evaluated parameters of tumor size, PTV dose, mean lung dose, and absolute and relative volumes of the lung exposed to minimum doses of 5-70 Gy were not correlated with early and late PFT changes. Subgroup analysis based on pre-SBRT PFTs (greater or equal and less than median) did not identify any dose-effect relationship.

Conclusions

This study failed to demonstrate a significant dose-effect relationship for changes of pulmonary function after SBRT for early-stage non-small cell lung cancer.

Introduction

Stereotactic body radiation therapy (SBRT) is the treatment of choice for medically inoperable patients with stage I non-small cell lung cancer (NSCLC). Prospective trials have reported local control rates in the range of 90% and higher, which is substantially better compared with conventionally fractionated radiation therapy (1). These high rates of local tumor control are achieved by hypofractionated, dose-escalated irradiation with biologically effective doses (BED) >100 Gy (calculated with α/β = 10 Gy) to the primary tumor. Most importantly, recent studies confirmed that this improvement in local control also translates into improved overall survival (2).

All steps of the SBRT work flow have been optimized during recent years, aiming at best possible accuracy. As a consequence, the exposure of healthy normal tissue to these high radiation doses is minimized. Nevertheless, SBRT might potentially result in increased pulmonary toxicity in a fragile patient population, for whom the most common reasons for inoperability are pulmonary comorbidities with decreased lung function.

Radiation-induced pneumonitis is the most frequent acute pulmonary toxicity: whereas the majority of patients develop asymptomatic grade 1 pneumonitis, clinically symptomatic pneumonitis is observed in <10%. Similar to conventionally fractionated radiation therapy, a dose-effect relationship has been demonstrated 3, 4, which provides the opportunity to estimate the individual patient risk at the time of treatment planning. Regarding late pulmonary toxicity, the majority of patients develop localized fibrosis in the high-dose region (5). This fibrosis is usually asymptomatic, and post-SBRT pulmonary function (PF) changes are therefore considered as a more clinically relevant endpoint.

We have recently established a multi-institutional database of image guided SBRT for early-stage NSCLC. Only a small loss of PF was observed within the first 2 years after SBRT; however, a large interpatient variability of post-SBRT PF changes was noted (6). It was therefore the aim of this study to investigate whether tumor and treatment parameters like tumor size, prescription dose, and irradiation exposure of the lung are associated with PF test (PFT) changes.

Section snippets

Methods and Materials

Between 1998 and 2010, a total of 483 patients with 505 tumors of early-stage NSCLC were treated with image guided SBRT at 1 of 5 international institutions [William Beaumont Hospital (WBH), The Netherlands Cancer Institute = Antoni van Leeuwenhoek Hospital (NKI-AVL), Thomas Jefferson University (TJU), Princess Margaret Hospital (PMH), University Hospital Wuerzburg (UHW)].

Results

Characteristics of the 191 patients analyzed in this study (Table 1) were not significantly different from the total population of 484 patients in our database, except for stage distribution and PET staging; differences in histology and number of SBRT fractions were of borderline significance (P=.06). Additionally, no differences in age, maximum GTV dimension, number of irradiation fractions, prescription dose, or baseline PFT values were observed between patient subgroups with availability of

Discussion

Our results based on a large number of patients confirm other studies that post-SBRT PF is either stable 9, 10, 11, 12, 13 or decreases only by a small amount 14, 15. Although these data are encouraging and further support the safety of SBRT, they need to be interpreted with caution.

First, PF was mostly assessed approximately 1 year after SBRT, and long-term data are scarce. Experiences from conventionally fractionated radiation therapy indicate that assessment of early PF is not sufficient.

Conclusions

No correlation between post-SBRT PFT changes and tumor size, treatment dose, and dose exposure of the lungs was observed in this multicenter analysis; early and late PF changes were independent from these clinical and treatment parameters. The absence of a dose-effect relationship may be explained by the combination of (1) a predominant influence of pre-existing pulmonary comorbidities on the PF, which could not be evaluated in this study, and (2) the damage of SBRT being sufficiently small

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Conflict of interest: This research was partially supported through an Elekta Stereotactic Research Grant, with all institutions being members of the Elekta Lung Research Group. This work and these data, however, are the intellectual property of the individual group members and their sponsoring institutions.

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