Clinical outcome of hypofractionated breath-hold image-guided SABR of primary lung tumors and lung metastases
- Judit Boda-Heggemann†1Email author,
- Anian Frauenfeld†1,
- Christel Weiss2,
- Anna Simeonova1,
- Christian Neumaier1,
- Kerstin Siebenlist1,
- Ulrike Attenberger3,
- Claus Peter Heußel4,
- Frank Schneider1,
- Frederik Wenz1 and
- Frank Lohr1
© Boda-Heggemann et al.; licensee BioMed Central Ltd. 2014
Received: 27 July 2013
Accepted: 23 December 2013
Published: 8 January 2014
Stereotactic Ablative RadioTherapy (SABR) of lung tumors/metastases has been shown to be an effective treatment modality with low toxicity. Outcome and toxicity were retrospectively evaluated in a unique single-institution cohort treated with intensity-modulated image-guided breath-hold SABR (igSABR) without external immobilization. The dose–response relationship is analyzed based on Biologically Equivalent Dose (BED).
Patients and methods
50 lesions in 43 patients with primary NSCLC (n = 27) or lung-metastases of various primaries (n = 16) were consecutively treated with igSABR with Active-Breathing-Coordinator (ABC®) and repeat-breath-hold cone-beam-CT. After an initial dose-finding/-escalation period, 5x12 Gy for peripheral lesions and single doses of 5 Gy to varying dose levels for central lesions were applied. Overall-survival (OS), progression-free-survival (PFS), progression pattern, local control (LC) and toxicity were analyzed.
The median BED2 was 83 Gy. 12 lesions were treated with a BED2 of <80 Gy, and 38 lesions with a BED2 of >80 Gy. Median follow-up was 15 months. Actuarial 1- and 2-year OS were 67% and 43%; respectively. Cause of death was non-disease-related in 27%. Actuarial 1- and 2-year PFS was 42% and 28%. Progression site was predominantly distant. Actuarial 1- and 2 year LC was 90% and 85%. LC showed a trend for a correlation to BED2 (p = 0.1167). Pneumonitis requiring conservative treatment occurred in 23%.
Intensity-modulated breath-hold igSABR results in high LC-rates and low toxicity in this unfavorable patient cohort with inoperable lung tumors or metastases. A BED2 of <80 Gy was associated with reduced local control.
Standard therapy for stage I-II lung cancer or solitary lung metastases is surgical resection. SABR (Stereotactic Ablative Radiotherapy) is a non-invasive, effective and low-toxicity alternative for medically inoperable patients .
SABR of lung lesions poses a special challenge for several reasons such as the highly volume-dependent radiosensitivity of healthy lung tissue and surrounding organs at risk (OAR, e.g. oesophagus, heart), breathing-induced motion of pulmonary targets and the dosimetrically difficult situation of a high-density tumor lesion surrounded by low-density lung tissue. The lung itself is one of the most radiation-sensitive organs with two different manifestations of radiation damage with different time frames. As a severe early (subacute) side effect of radiation therapy, pneumonitis occurs in 5-15% 4–6 weeks after conventionally fractionated large-volume thoracic irradiation. The incidence of radiation pneumonitis depends on the radiation dose and the irradiated volume of the normal lung tissue . As a late side effect and consequence of radiation pneumonitis, pulmonary fibrosis may arise, rendering the affected tissue without function.
In spite of potentially serious side effects, dose escalation is the most important part of improvement of local control of lung targets and therefore should be aimed at  since both model calculations  and clinical data suggest that doses necessary for tumor ablation are higher than initially thought . To reliably and accurately create the required highly conformal radiation doses necessary for lung target irradiation, improvement of imaging, planning, dose calculation and delivery tools is needed.
The development of devices that enable image guided radiotherapy (IGRT) together with non-invasive lung immobilization makes a “frameless” stereotactic approach possible . Breath-hold techniques for tumor immobilisation facilitate the delivery of high doses to the PTV while maximally sparing OAR . Dosimetric comparisons between free-breathing and breath hold radiotherapy for lung cancer  have shown an improved target conformity index and less dose to the heart and healthy lung if compared to free breathing planning. Computer-controlled breath-hold with the ABC®-system (Active Breathing Coordinator, Elekta AB, Stockholm, Sweden) in combination with daily image-guidance has been successfully implemented for targets that move with spontaneous breathing .
Recent pooled analyses of almost 500 patients with stage I NSCLC have shown excellent results with local control rates of 92% and low toxicity . Other large multicenter trials, for example the RTOG 1021 trial, comparing the sublobular resection with SABR in patient cohorts, with high risk of complications with more extensive surgery are currently in progress.
In this retrospective evaluation, we assess outcome and toxicity in a unique single-institution series of patients who received volume-image-guided, intensity modulated breath-hold lung SABR with both primary lung and metastatic lesions, undergoing no external immobilization.
Patients and methods
Patients (n = 43) characteristics
Ys, Median; (range)
Lung metastasis of various primary tumors
Further characteristics of patients with NSCLC (n = 27)
Histologic diagnosis Squamous cell carcinoma Adenocarcinoma others
9 (33%) 13 (48%) 5 (19%)
Chemotherapy before or after RT
Pulmonary disease (COPD)
None of the above
Data were evaluated retrospectively regarding overall survival (OS), progression-free-survival (PFS), progression pattern, local control (LC), acute and late toxicity based on clinical symptoms and CTC/LENT-SOMA scales.
Radiotherapy planning, dose calculation and treatment
Planning CT scans were acquired with a spiral-CT (Somatom Emotion, Siemens, Erlangen, Germany, thereafter Brilliance Big Bore Oncology, Philips, Hamburg, Germany) after an initial patient training session in inspiratory breath-hold at approximately 70% of vital capacity with ABC® . Radiotherapy planning was initially performed as manually weighted Intensity Modulated RadioTherapy (IMRT) with OTP (Theranostic GmbH, Solingen, Germany) and thereafter with inverse planned step-and-shoot IMRT or VMAT (Volumetric Modulated Radiotherapy) with Monaco® (Elekta AB, Stockholm, Sweden).
PTV was calculated from CTV by adding a 5 mm margin radially and 10 mm in the craniocaudal direction to compensate residual intrafractional error of the ABC®-based positioning .
Dose calculation was performed initially by a pencil beam (PB) algorithm (11 patients), thereafter both with PB and collapsed cone (CC) algorithms (32 patients). After the change to CC algorithm, the PB was still calculated in order to compare the resulting nominal dose distributions.
Healthy lung V15
Healthy lung V20
Spinal cord Dmax
Trachea/main bronchus Dmax
Brachial plexus Dmax
Ribs/Thoracic wall Dmax
Heart and major vessels Dmax
PTV-coverage was analysed based on relevant parameters (D99 (dose encompassing 99% of the PTV), minimal, maximal, mean and median PTV-dose.
Implementing results from published literature reports [5, 13–16] regarding dose escalation and fractionation, dose to the patients was adjusted during the reported period and varied between single-fraction doses of 20-26 Gy initially (depending on tumor and healthy lung volume) and various hypofractionated regimens with the current, final protocol prescribing 5x12 Gy every other day to peripheral tumors and 12x5 Gy to central lesions . For exact fractionation schedules of each lesion, see Additional file 1: Table S1.
To be able to retrospectively compare these various fractionation regimens, we introduced Biologically Effective Dose in 2 Gy fractions (BED2 ). BED2 was calculated  with an assumed α/β ratio of 10 with the following formula: BED2 = Dx(d + α/β)/(2 + α/β).
Patients were treated as described previously . Shortly, a linac with 6MV photons was used (Synergy®, Elekta AB, Stockholm, Sweden). Daily image-guidance was performed with EPIDs (Electronic Portal Imaging Device) and since 2005 with repeat breath-hold CBCT (XVI®, Elekta AB, Stockholm, Sweden [17, 19]). Planning-CT images were matched online with the daily CBCT images using manual fusion with respect to soft-tissue anatomy . Online surveillance of breath-hold was performed based on the continuous acquisition of MV-frames during irradiation allowing position verification of the tumor itself, if possible, or of a surrogate structure such as the diaphragm .
Patient follow-up (FU) was scheduled 6 weeks after radiotherapy and every 3 months thereafter with clinical examination and thoracic CT with i.v. contrast. An assessment of tumor response was performed using the RECIST (Response Evaluation and Criteria in Solid Tumors) criteria. Response was graded as complete response (CR), partial response (PR), stable disease (SD) or progression.
Acute (first 90days) and late toxicity (>90 days) was evaluated based on clinical symptoms (graded based on the CTC-scale in the acute phase and on the LENT-SOMA criteria (late effects in normal tissues subjective, objective, management and analytic scales) in the late phase). Recorded clinical symptoms were general condition, coughing, dyspnoea, pneumonitis, pulmonary oedema, dysphagia, pleural effusion, fever and skin symptoms for assessing acute toxicity; rib fracture, pulmonary fibrosis, thoracic pain, dyspnoea and coughing for late toxicity. Pneumonitis analysis was based on presence of symptoms requiring treatment and thoracic CT imaging.
Statistical analysis was performed with the SAS-software, release 9.01 (SAS, Cary, NC, USA). OS (Overall-Survival), PFS (Progression-Free-Survival) and LC (Local Control) were recorded and subject to actuarial analysis. OS was calculated from the day of irradiation until either the day of death (event) or the day of the last FU (censored data). PFS was calculated from the day of irradiation until either the day of relapse or death (events) or the last FU without relapse (censored data when at the last FU the patient lived without any evidence of progression). LC was calculated from the day of irradiation until either the day of local progression (event) or the last FU/death without local progression (censored data). For LC, number of patients at risk was calculated for each time point. Kaplan-Meier-plots for OS, PFS and LC were calculated in order to assess median survival/control times. Correlation of the local control time with PTV size and BED2 was analysed by the Kaplan-Meier log-rank test. P-values < 0.05 were considered as significant, 0.05 < p < 0.15 as a trend to significance.
All patients managed to achieve sufficient repeat breath-hold with ABC®.
Mean BED2 (Biologically Effective Dose) was 87±20 Gy (median 83 Gy). 12 lesions were treated with a BED2 of <80 Gy, and 38 lesions with a BED2 of >80 Gy (range 50-150 Gy). PTV-volume was 94±90 cm3 (median 69 cm3).
Follow-up (FU), Overall-Survival (OS), Progression-free-survival (PFS) and Local Control (LC)
Median follow-up (FU) was 15 months for all patients. Median FU was 24 months for living patients. 12 patients are alive, 31 patients have died.
Actuarial 1-year LC was 91% (34 patients at risk; CI: 82% - 99%) and 2-year LC was 86% (21 patients at risk; CI: 73% - 98%; Figure 1C). 95% of the lesions treated with a BED2 > 80 Gy were controlled locally after one year. No local relapses at doses >90 Gy BED2 were observed. Local progression was observed in only 5 cases, mainly in the initial dose finding phase, in one patient with an only retrospectively recognized pleural invasion of the irradiated lesion and in one patient with an extremely large PTV. Disregarding this case, the variation in PTV was not extensive (upper limit of tumor diameter: 5 cm) and no statistically significant influence of PTV size on local control was found in the range of diameters treated within this series. Several dose cut off values were tested statistically. Lesions with a BED2 > 80 Gy showed a trend for better local control (Figure 1D) than lesions treated with BED2 < 80 Gy. With the limited patient number, the difference is not statistically significant (p = 0.1167, Kaplan-Meier log rank). A comparison between NSCLC and patients with metastases did not show statistically significant difference in LC.
Most patients died due to systemic metastases with locally controlled irradiated lesions.
7 patients had radiological signs of pneumonitis but no clinical symptoms (grade 1). Clinically apparent pneumonitis (requiring steroid treatment) was present in 23% (n = 9) of the treated patients. In six patients it was considered grade 2, while three patients developed a respiratory insufficiency as a consequence of their pneumonitis (grade 3). Two of them had suffered from severe chronic obstructive lung disease (COPD) before treatment and one of them already had a partial respiratory insufficiency. After conservative treatment of the grade 3 pneumonitis the functional condition of the patients was restituted to the pre-SABR state.
Dyspnea and coughing as side effect in the acute and chronic phase after SABR, classified by CTC
Acute toxicity, reported separately for NSCLC (n = 27) and metastases (n = 16); dyspnea and coughing as grade difference between pre-therapeutic state and acute phase
Late toxicity was difficult to analyse in this cohort of patients with advanced tumor stages due to progressive disease causing symptoms similar to radiation-induced changes. No rib fractures were observed. Radiation induced fibrosis LENT-SOMA grade 1 was observed in 12 patients in the follow-up CT, however, patients were clinically inapparent. After SABR, 6 patients developed chronic cough grade 1, with half of them already suffering from chronic bronchitis and COPD prior to SABR. In the patients alive at analysis, no change in dyspnea was registered in the chronic phase, when compared to that in the acute phase. However, evaluation is difficult (4 patients had died and 2 patients were lost to clinical FU).
Literature overview SABR, mixed populations (tp = time point, * = only NSCLC stage I, -: not stated)
Wulf et al. 
50 Gy BED2
76% (1 y) 61-76% (2 y)
Hara et al. 
50-125 Gy BED2
77% (1 y) 41% (2 y)
93% (1 y) 78% (2 y)
Yoon et al. 
50-88 Gy BED2
51% (2 y)*
81% (2 y)
82% (2 y)
Milano et al. 
31-72 Gy BED2
77% (2 y) 73% (4 y)
Norihisa et al. 
~75 Gy BED2
84% (2 y)
35% (2 y)
90% (2 y)
Salazar et al. 
109 NSCLC I-IV + oligometastases
120 Gy BED2
81% (2 y)* 48% (5 y)*
Rusthoven et al. 
104-150 Gy BED2
39% (2 y)
100% (1 y) 96% (2 y)
McCammon et al. 
150 Gy BED2
89% (>54 Gy, 3 yr)
Bradley et al. 
91 NSCLC I/II
71-126 Gy BED2
58% (3 y)
71% (3 y)
86% (2 y)
Duncker-Rohr et al. 
45 lung (NSCLC and metastases)
49.5-70.3 Gy BED2
52,7% (2 y)
80,5 (2 y)
Inoe et al. 
106 Gy BED10 (30-168 Gy range)
47% (2 y) 32% (3 y)
40% (2 y) 32% (3 y)
80% (2 and 3 y)
Inoe et al. 
109 NSCLC I
66 Gy BED2
64% (5 y)
10% (5 y), intrathoracal progression
78% (5 y)
Verstegen et al. , SABR arm
64 NSCLC I-II
>100 Gy BED10
91.8% (1 y) 79.6% (3 y)
91.6% (1 y) 85.2% (3 y)
96.8% (1 y) 93.3% (3 y)
Kim et al. 
16 NSCLC I
88 Gy BED2 96 Gy BED2
87.5% (1.5 y)
85.2% (1.5 y)
91% (1.5 y)
Shioyama et al. 
8 SCLC stage I
88 Gy BED2
72% (3 y)
71% (3 y)
100% (3 y)
Grills et al. 
505 NSCLC I-IIB
132 Gy BED10
60% (2 y)
80% (2 y) 79% (3 y), distant metastases
94% (2 y)
Despite our negatively selected patient cohort (high percentage of metastases of different primaries and 40% > Stage IIIA primary lung cancers), a 2-yr LC of 85% was achievable, which is comparable with the results in the literature in more favourably selected patients. LC in our cohort was independent of being a primary lung tumor or a metastasis, while available reports have suggested better results for (albeit typically earlier stage) primary lung tumors . Regarding tumor-entities, our cohort was heterogeneous. This is, however, a situation similarly encountered in other SABR-series (e.g. [27, 45]).
PFS at 2 years of 28% in our cohort is lower than published for early stage NSCLC (52-86%, [1, 15, 21, 36–43]) or mixed cohorts (37-81%, [5, 16, 22–28]). This is probably due to the extremely negatively selected patients (all stages included) and high percentage of metastases. Progression occurred in mediastinal lymph nodes (12%; similar to literature reports ), or distantly (78%). Distant metastases indicate a clear need for detailed pretreatment staging (e.g. PET), appropriate selection criteria of patients for SABR alone and improving systemic therapy .
A 2-yr OS of 43% in our cohort is comparable with literature data (30-78% for NSCLC alone and 30-84% for mixed cohorts) with cause of death mainly being distant progress (42%), as in most series. This relatively long OS validates the LC data that might otherwise be biased by the chance of relapse being reduced by short survival.
This series suggests improved LC with higher doses, particularly if a BED2 > 80 Gy was applied, though this difference did not reach statistical significance in this relatively small cohort. LC after 1 year was maintained in >95% of the lesions which had been treated with a BED2 > 90 Gy. The reason for the nominally low “threshold” dose for durable local control may be found in the very high precision in dose delivery using igSABR, thus reducing the amount of “lost” dose. Similar results were reported in a recent manuscript by Duncker-Rohr et al.  with 2-yr LC of 95% (NSCLC) and 59,7% (metastases). Ablation doses might therefore not be as high as assumed at a time when treatment delivery was less spatially precise .
Toxicity was low despite many comparatively large lesions in the series. In RTOG-0236, grade 3 and 4 pulmonal side effects were recorded. In our cohort, no worsening of post-therapeutic symptoms > grade 3 (if compared to pre-therapeutic symptoms) was recorded. We did not observe any rib fractures [13, 41] or skin toxicity > grade 2. RTOG 0915 will provide further insight as to what fractionation regimen to use, comparing different fractionation patterns regarding grade 3 toxicities.
Normal lung tolerance forbids, however, the application of very high doses for centrally located or very large tumors (>5 cm); which results in more frequent local relapses in such larger GTVs . The results of RTOG-0813 should provide us with a recommendation for an effective dose that can be applied to Stage I central lesions with acceptable toxicity. Additional dose escalation in the future may be possible by further PTV-margin reduction through improvement and clinical integration of immobilization/tracking methods (breath hold, gating, online tracking ). If currently prohibitive technical limitations in beam application are overcome and immobilization and imaging methods known from photon therapy can be implemented successfully, particle therapy might further improve efficacy [49–53].
Regarding the role of adjuvant chemotherapy in addition to SABR, CALGB and RTOG are currently preparing respective trials . In addition, antibodies, biologicals and radiosensitisers are also under investigation [55, 56].
Intensity modulated, image-guided breath-hold SABR is an effective non-invasive treatment modality that enables the application of reasonably high BED2 which in turn results in a high local control rate and relatively low toxicity in this negatively selected cohort of patients with inoperable lung tumors and lung metastases. Doses for tumor ablation may be lower than assumed at a time when delivery techniques were less precise. As disease progression was mainly outside the treated area, systemic therapy has to be further optimized in conjunction with SABR.
We thank all referring physicians (Drs Ludwig, Fröhlich, Killian, Weingärtner, Jäckel, Ort, Heil, Weihrauch, Schneider, Brust/Schuster/Plöger/Hensel, Hofmann, Schneider, Faul-Sprenger/Maser, Reis/Limbeck/Meissner, Boos, Gram, Bossert/Träger, Alting and Hällfritzsch (all Mannheim); Maurer (Weinheim), Schulz-Jacob (Rennerod), Heni/Weiss (Ludwigshafen), Schmidt/Langer (Waldbrunn-Westerwald), Meinecke-Wieland (Bad Wimpfen), Dreiner (Bad Rappenau), Gengnagel/Kessler-Holz (Darmstadt), Vothknecht (Schlangen), Massner (Frankenthal)) and institutions (St. Marien-KH Ludwigshafen, St.-Vincent Hospiz Mannheim, KH St Vincencz Limburg/Lahn, KKH Frankenthal, Hospiz Homburg, Universitätsklinik Homburg, Klinikum Darmstadt, Klinikum Karlsbad-Langensteinbach) for providing clinical information and radiological material. We thank Mr. Marat Bernhard, Ms. Iris Kalish und Ms. Beate Schweizer for providing excellent technical support with ABC® and CBCT. We thank Ms. Erika Filp, Ms. Doris Richter and Ms. Sabine Mendel for management of archived patient data. Parts of these studies were supported by a research grant from Elekta Inc. JBH is supported by the “Ministerium für Bildung und Forschung, Baden-Württemberg“and the ESF (European Social Funds).
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