Stereotactic body radiotherapy using gated radiotherapy with real-time tumor-tracking for stage I non-small cell lung cancer
© Inoue et al.; licensee BioMed Central Ltd. 2013
Received: 30 November 2012
Accepted: 18 March 2013
Published: 21 March 2013
To clarify the clinical outcomes of two dose schedule of stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC) using a real-time tumor-tracking radiation therapy (RTRT) system in single institution.
Using a superposition algorithm, we administered 48 Gy in 4 fractions at the isocenter in 2005–2006 and 40 Gy in 4 fractions to the 95% volume of PTV in 2007–2010 with a treatment period of 4 to 7 days. Target volume margins were fixed irrespective of the tumor amplitude.
In total, 109 patients (79 T1N0M0 and 30 T2N0M0). With a median follow-up period of 25 months (range, 4 to 72 months), the 5-year local control rate (LC) was 78% and the 5-year overall survival rate (OS) was 64%. Grade 2, 3, 4, and 5 radiation pneumonitis (RP) was experienced by 15 (13.8%), 3 (2.8%), 0, and 0 patients, respectively. The mean lung dose (MLD) and the volume of lung receiving 20 Gy (V20) were significantly higher in patients with RP Grade 2/3 than in those with RP Grade 0/1 (MLD p = 0.002, V20 p = 0.003). There was no correlation between larger maximum amplitude of marker movement and larger PTV (r = 0.137), MLD (r = 0.046), or V20 (r = 0.158).
SBRT using the RTRT system achieved LC and OS comparable to other SBRT studies with very low incidence of RP, which was consistent with the small MLD and V20 irrespective of tumor amplitude. For stage I NSCLC, SBRT using RTRT was suggested to be reliable and effective, especially for patients with large amplitude of tumor movement.
Stereotactic body radiotherapy (SBRT) with high local dose has been applied to extra-cranial diseases such as peripheral stage I non-small cell lung cancer (NSCLC) and has been reported to provide excellent local control and survival compatible with surgery [1, 2].
Respiratory motion of lung tumors has been one of the largest uncertainties in the radiotherapy of lung cancers . Considering respiratory motion, there are several irradiation methods: (i) irradiation with breath coaching and holding [4–7], (ii) irradiation with respiratory gating using external surrogates with four-dimensional CT , (iii) immobilization in the stereotactic body frame (Elekta, Stockholm, Sweden) with an abdominal compression device to limit respiratory motion during radiotherapy [8, 9], (iv) irradiation using planning CT with a slow scan technique [10, 11], (v) pursuing irradiation with some prediction models [12–17], (vi) and real-time tumor-tracking radiotherapy (RTRT) system .
A prototype RTRT was developed at our institute in 1999 to increase the precision of irradiation for moving lung tumors. Real-time tumor-tracking radiotherapy comprises two different concepts: (i) pursuing irradiation where the therapeutic beam changes its direction during treatment; and (ii) interrupting irradiation where the therapeutic beam does not change its direction during treatment. The prototype RTRT system used the interrupting irradiation method. We clinically used the prototype RTRT system in which the linear accelerator is gated to irradiate the tumor only when the implanted fiducial marker is within 2 mm from its planned position [19, 20]. We have published a study showing steep dose–response curve between 40 Gy and 48 Gy in four fractions in one week in patients with stage I NSCLC treated with RTRT between 2000 and 2005 in our institution . In that study, we showed that 48Gy at the isocenter with 5 mm CTV-PTV margin, irrespective of amplitude of tumor motion, was safe and effective. Since then, dose calculation software has been upgraded to superposition algorithm from Clarkson algorithm, resulting in a certain difference in dose prescription method. The aim of the present study was to clarify the clinical outcomes of SBRT for stage I NSCLC using this RTRT system using dose calculation method with inhomogeneity correction between 2005 and 2010.
Squamous cell carcinoma
Large cell carcinoma
Tumor size (mm)
Tumor site (n)
T stage (n)
FDG-PET before SBRT (n)
Dose prescription (n)
48Gy/4fr at isocenter
40Gy/4fr to the 95% volume of PTV
All patients received SBRT to NSCLC using the RTRT system. The RTRT system has been described in detail elsewhere [18–20]. In brief, 1.5-mm gold markers were implanted near the tumor by bronchoscopy. CT scans were taken with the patients holding their breath at the end of normal expiration. The gross tumor volume (GTV) was defined using multi-slice CT taken at the end of expiration during breath holding. Giraud et al. reported that CTV margins must be increased to 8 mm and 6 mm for adenocarcinoma and squamous cell carcinoma . Based on their report, we defined the clinical target volume (CTV) as the GTV plus 6 mm for squamous cell carcinoma, 8 mm for adenocarcinoma, and 5 mm for others where no appropriate basic literature had existed. The planning target volume (PTV) was the CTV plus a 5-mm margin irrespective of the amplitude of the tumor. The PTV margins were fixed irrespective of the tumor amplitude because RTRT is gated to irradiate the tumor only when the implanted fiducial marker is within 2 mm from its planned position. Therefore, the target volume did not increase when the tumor movement was large, especially in the lower lobe. In our RTRT system, the irradiated volume depended only on tumor size. The position of multileaf collimator sets was usually the PTV plus a 5-mm margin.
Using a superposition algorithm, we administered 48 Gy in 4 fractions at the isocenter in 2005–2006 (n = 30) and 40 Gy in 4 fractions to the 95% volume of PTV in 2007–2010 (n = 79) with a treatment period of 4 to 7 days. Isocenter dose of 40 Gy in 4 fractions to the 95% volume of PTV was approximately ranged from 45 to 50 Gy.
Follow-up after SBRT
Follow-up visits were usually every 3 months after SBRT. CT scans were usually performed every 3 to 6 months after SBRT. Distinguishing between residual tumor tissue and radiation fibrosis was difficult. Local disease recurrence was considered to have occurred only when enlargement of the local tumor continued for > 6 months on follow-up CT scans. FDG-PET and/or histologic confirmation was recommended when local recurrence was suspected, but this was not mandatory. Absence of local disease recurrence was defined as locally controlled disease.
Written informed consent to receive SBRT was obtained from all patients. This retrospective study was approved by the ethics committee of Hokkaido university hospital. This study was performed in accordance with the 1975 Declaration of Helsinki, as revised in 2000.
The overall survival (OS) and the local control (LC) rates were calculated using the Kaplan-Meier method. The log-rank test was used to calculate the statistical significance of differences. Multivariate analysis was performed using a Cox proportional hazards regression model. The difference of means was analyzed with Student’s t-test. A value of p < 0.05 was considered to be statistically significant. R version 2.14.2 with the survival packages (R project for statistical computing, Vienna, Austria) was used for statistical analyses.
Local control and survival
Univariate analyses for local control (LC) and overall survival (OS)
Lower lobe vs. others
Female vs. others
T1a vs. others
Adenocarcinoma vs. others
Maximum amplitude of marker movement
≥ 3 cm vs. < 3 cm
FDG-PET before SBRT (n)
yes vs. no
Dose prescription (n)
48Gy/4fr at isocenter vs. 40Gy/4fr to the 95% volume of PTV
Multivariate analyses for local control (LC) and overall survival (OS)
Female vs. others
T1a vs. others
Maximum amplitude of the marker movement
≥ 3 cm vs. < 3 cm
Insertion of the gold markers by bronchoscopy
No complications were occurred when gold markers were implanted near the tumor by bronchoscopy. No inter-fractional migrations of gold markers were occurred.
Amplitude of respiratory tumor motion
Breath coaching and holding using stereotactic body frame has been used as a simple method for SBRT without gating of radiotherapy . However, the effectiveness of visual coaching for tumor localization is still debatable, because of the variations in observers, lengths of observation times, and reproducibility [6, 23, 24]. Four-dimensional CT with a respiratory gating system using external surrogates has been expected to be useful for respiratory gating. The combination of external surrogates and internal observation with simple prediction models was suggested to reduce the residual motion of the tumor in a simulation study . However, the four-dimensional CT images are all vulnerable to problems relating to the lack of correlation between external surrogates and internal tumor positions during breathing [26–28]. Immobilization in the stereotactic body frame with an abdominal compression device has been used widely [8, 9]; however, internal stabilization of tumor location is not certain yet. Planning CT with a slow scan technique can visualize a major part of the trajectory of the tumor by scanning each slice for a time longer than the respiratory cycle [10, 11]. With this method, internal target volume can be quite large when the tumor movement is large. Tracking irradiation dynamically pursuing the target with some prediction models has been developed recently bus is still having uncertainty in the modeling of respiratory motion of the tumor [12–17].
The RTRT system potentially resolves these problems described above. With implantation of internal fiducial markers by bronchoscopy, the correlation between internal fiducial markers and internal tumor positions during breathing is more reliable than in the case of external surrogates. Even in the patients with large tumor movement, the target volume margins can be always fixed irrespective of the tumor amplitude. Therefore, target volume does not increase even when the tumor with large movement, which often occurs especially in the lower lobe. Irradiated volume depended only on tumor size using RTRT. Thus, RTRT has potential to reduce the incidence of adverse effect for lung without compromising tumor control comparing other SBRT technology. However, migration of fiducial markers in lung is the potential risk to induce systematic error resulting in higher local relapse rate if we do not take enough care at the daily set-up of the patient . These theoretical advantage and potential disadvantage of SBRT using RTRT system and internal fiducial markers has been debatable.
Insertion of gold markers by bronchoscope is essential for RTRT. Pneumothorax and/or bleeding sometimes occur in trans-bronchial biopsy (TBB) by bronchoscope; however insertion of the gold markers by bronchoscope is much safer than TBB. Pneumothorax and/or bleeding rarely occur in insertion of gold markers by bronchoscope. Imura et al. also reported that markers dropped within the first week after insertion at a high rate and at a much lower rate 1 week after insertion . We usually start RTRT at least 1 week after insertion of the gold markers.
Studies of stereotactic body radiotherapy for stage I non-small cell lung cancer
Dose* median follow-up
83 (T1 only)
93 (T1 only)
90 (T1 only)
48(i) or 40(p)
It was very difficult in distinguishing radiation pneumonitis/fibrosis with local recurrence. Local disease recurrence was considered to have occurred only when enlargement of the local tumor continued for > 6 months on follow-up CT scans. FDG-PET and/or histologic confirmation was recommended when local recurrence was suspected. We considered that tumor enlargement only for 3 months might be false positive for local recurrence. In our experience, six months or larger period were thought to be suitable for judgment of the local recurrence. The definition of local control was uncertain in radiotherapy compared with surgical resection.
Matsuo et al. reported that tumor diameter and sex were the most significant prognostic factors in SBRT for NSCLC . In this study, multivariate analysis demonstrated that only the tumor diameter ( ≤ / > 2 cm) was a significant factor in OS. Li et al. reported that FDG-PET/CT was specific in N0 staging for T1–2 NSCLC and the negative predictive value was about 91% in clinical N0 patients, suggested that FDG-PET/CT may help to accurately stage N0 patients and thus identify patients for SBRT . However, there was no statistical significant difference in OS between patients underwent FDG-PET scan before SBRT and those did not in this study.
Grade 3 RP occurred in 2.8% of cases in the present study. The incidence of Grade 3 or greater RP in literature distributed from 0% to 4.9% for patients with stage I NSCLC [2, 10, 21, 31, 38]. The severity and incidence of RP in the present study in the present was similar to previous SBRT studies using a similar dose. Timmerman et al. reported a higher incidence of Grade 3 or higher-grade RP of 16.4% with a higher 3-year LC of 97.6% after administering a higher dose of 54 Gy in 3 fractions . The present results indicate that when using SBRT with RTRT the dose to the target may be able to be increased from 48 Gy in 4 fractions to a higher dose such as 54 Gy in 3 fractions and the LC could be improved with a reduction in the incidence of Grade 3 or higher-grade RP. Since the incidence of RP in other SBRT studies is so low, it is not certain yet whether RTRT is any better than other SBRT technology for reducing the incidence of RP by means of a higher dose.
MLD and V20 of the lung volume minus target volume were reported as risk factors of RP [39–43]. Palma et al. also reported that predictors of fatal pneumonitis were daily dose > 2 Gy, V20, and lower lobe tumor location . Comparing non-gated radiotherapy which includes the range of motion adding to CTV to create PTV, the size of PTV is smaller in gated radiotherapy using RTRT in principle irrespective of the tumor amplitude and tumor location. Consequently, MLD and V20 of the lung volume minus PTV should be smaller in the gated radiotherapy using RTRT. Barriger et al. reported that median MLD and V20 were 4.1 Gy and 4% for patients with NSCLC treated by SBRT, respectively . They also reported that median MLD was 5 Gy in patients with RP Grade 2–4, compared with 4 Gy in those with RP Grade 0/1, and median V20 was 6.6% in patients with RP Grade 2–4, compared with 4% in those with RP Grade 0/1, respectively, which were similar to our present study. In the present study, although the maximum amplitude of the marker movement of the lower lobe was significantly greater than that of upper lobe, there was no correlation between larger maximum amplitude of marker movement and larger PTV, MLD, or V20. Present study suggested that SBRT with gated radiotherapy using RTRT system was effective to reduce MLD and V20 and thus the risk of RP consequently.
In this study, we showed the clinical outcomes of SBRT using RTRT for Stage I NSCLC and found that there was no correlation between larger maximum amplitude of marker movement and larger PTV, MLD, or V20. These are risk factors of RP; therefore, RTRT is thought to be useful especially in cases of large amplitude of tumor movement.
Using only a 5-mm PTV margin to CTV without additional margin for organ motion, SBRT using the RTRT system achieved LC and OS comparable to other SBRT series with very low incidence of RP, which was consistent with the small MLD and V20 irrespective of the tumor amplitude. For stage-I NSCLC, SBRT using RTRT was suggested to be reliable and effective, especially for patients with large amplitude of tumor movement.
This research is partly supported by the “Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program),” initiated by the Council for Science and Technology Policy (CSTP).
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