We investigated the clinical outcomes and dosimetric parameters of patients with primary or metastatic lung cancer who received multiple courses of SBRT, to evaluate its efficacy and safety, along with predictors of lung toxicity. The second and third courses of SBRT (performed using the CyberKnife®) showed favorable LC and OS, which suggests the effectiveness of such treatment. After repeated SBRT, Grade 2+ RP was frequently observed; a fatal case was experienced. We showed that the MLD and absolute lung volume spared from low-dose irradiation can predict lung toxicity by analyzing composite plans based on EQD2.
In a review by De Bari et al., the 1-year and 2-year LC rates after second thoracic SBRT for primary or metastatic cancer ranged between 59–95% and 50–92%, respectively [16]. A large case series reported that a second course of radiotherapy with 50 Gy in four fractions (BED10, 112.5 Gy) showed a 1-year LC of 95.0% [11]. We performed repeated SBRT (median BED10, 132.0 Gy) and demonstrated excellent LC, which indicated that CyberKnife® -based SBRT, as a repeated radical treatment, provides durable tumor control. The 1-year and 2-year OS rates following the last course of SBRT for patients with primary or metastatic cancer, have been reported to be in the range of 59–80% and 29–74%, respectively [16], which is comparable with our results.
Lung SBRT has been considered a safe treatment with minimal toxicity. For single course SBRT, the rates of Grade 2+ and Grade 3+ lung toxicity have been reported to be 9.1% (7.15–11.4%) and 1.8% (1.3–2.5%), respectively [17]. However, the safety of multicourse SBRT is not well understood. Several retrospective studies of thoracic re-irradiation have reported high rates of Grade 2+ and Grade 3+ RP, of 13.6–50.0% and 3.0–28.0%, respectively [7, 10, 12, 16, 18]. In our study, Grade 2+ and Grade 3+ pulmonary toxicity after repeated SBRT was observed in 25.0% and 8.0% of patients, respectively, which is consistent with previous reports. Our data also suggest a concern for increased pulmonary toxicity with multiple courses of lung SBRT, compared with single course SBRT.
We experienced a fatal RP that developed after repeated SBRT. Previous reports have identified few Grade 5 RPs in patients who received SBRT after previous conventional fractionated radiotherapy [11, 13]. There are no previous reports of fatal RP following multicourse SBRT. Analysis of a large case series reported that Grade 5 RP after a single course of SBRT occurred very rarely (1.3%) [19]. In that study, interstitial changes were observed retrospectively in 73.7% of Grade 5 RP patients, indicating a potential risk factor for fatal pulmonary toxicity. In our study, Grade 5 RP occurred in one of three patients with interstitial shadow; it was not observed in patients without interstitial shadow (33.3% vs. 0.0%; p = 0.015). Even in the context of multicourse SBRT, interstitial changes may be a risk factor for fatal toxicity.
Several risk factors for pulmonary toxicity in repeated thoracic radiotherapy have been identified. Out-of-field relapse [7], short interval between initial radiotherapy and second SBRT [18], poor performance status, impaired lung function, and initial PTV location in the bilateral mediastinum [11] have been indicated as risk factors for RP. In our study, there was no significant association between clinical factors and lung toxicity. Other similar studies have used different population backgrounds and clinical scenarios, which makes it difficult to obtain consistent results.
There are several reports on the correlation between RP and lung DVH parameters in the context of a second course of thoracic radiotherapy using SBRT. Liu et al. reported the dosimetric predictors of lung toxicity in 72 patients who underwent SBRT after conventional fractioned irradiation [11]. The composite V10, V20, V30, V40, and MLD were significantly correlated with the development of Grade 3+ RP. High composite MLDs were correlated with lung toxicity, which is consistent with our study. Muller et al. analyzed the DVH parameter associated with RP after multiple courses of SBRT, using a composite plan based on EQD2 (α / β = 3) [18]. In multivariate analysis, a trend was observed between composite lung V5 and the development of Grade 2+ RP (hazard ratio, 1.157; p = 0.058). Among the irradiated relative lung volumes that we investigated, composite V30 showed a weak trend of association with Grade 2+ RP. The accumulated lung dose may have a clinical impact on patients receiving multiple courses of SBRT.
In previous SBRT studies, lung dose has been assessed using irradiated relative volume (%). Our report is the first to show a significant association between absolute lung volume spared from low-dose irradiation and SBRT-induced lung toxicity. A correlation between decreased VS5 (<1,500 cc) and the development of Grade 3+ RP in conventional fractionated irradiation for primary lung cancer has been previously shown by Tsujino et al. [20]. Our entire cohort of Grade 2+ RP had VS5 < 1,500 cc; reduced VS5 correlated with the development of Grade 2+ RP. However, among the DVH parameters we examined, VS15 was the most strongly associated with RP. Due to SBRT's unique fractionation scheme and dose distribution, the DVH parameter that predicts RP in SBRT may differ from that of conventional fractionated radiotherapy.
This study has several limitations. Due to it being a retrospective analysis at a single institute, there are inherent biases, a small number of events, and an inhomogeneous study population. This may limit the power of the analyses and cause under-reporting of adverse events. Also, we included patients with primary lung cancer and with metastatic lung cancer, which makes it difficult to draw reliable conclusions about survival. Prospective studies with larger populations are needed for more precise assessment. Moreover, deformable image registration (DIR) was not available for generating the composite plans of our study. DIR is an image processing technique that can provide a more accurate assessment of the cumulative radiation doses to the lungs by accounting for anatomical changes [21, 22].