Because local control (LC) and survival have shown limited improvement after conventionally fractionated radiotherapy for early inoperable lung tumors, interest in alternative, hypofractionated treatment schedules has increased. Stereotactic ablative radiotherapy (SABR) has been effective for primary lung tumors, as well as pulmonary metastases that are associated with other primary organs.1, 2 In early studies, biological effective doses (BEDs) to the tumor with an alpha/beta ratio of 10 (BED10) greater than 100 Gy given in 3 or 4 fractions resulted in better LC and improved overall survival (OS) compared with conventional radiotherapy.3, 4, 5 However, this potential therapeutic gain can come with a risk of increased toxicities including fatal events, although they are usually rare.6 Proximity to the trachea or main bronchi, within 1–2 cm of the tracheobronchial tree (TBT), is directly related to increased toxicities observed clinically.6, 7, 8 As a result, highly fractionated ablative schedules such as 54 Gy in 3 fractions should not be used for centrally located thoracic tumors with such proximity.
Recently, the highly anticipated NRG Oncology/ Radiation Therapy Oncology Group (RTOG) 0813 trial was published.9 The maximally tolerated dose of 12 Gy per fraction over 5 fractions was reached in the study; however, the dose-limiting toxicity rate of 7.2% still gives certain clinicians pause for using a 5-fraction regimen, especially for “ultra-central” lesions.10, 11, 12, 13 A more fractionated dosing scheme and strict adherence to the organs-at-risk constraints may still need to be defined, especially for tumors that directly invade critical structures. A phase II prospective study (LungTech) by the European Organisation for Research and Treatment of Cancer using 60 Gy in 8 fractions for central lung tumors is ongoing; another Canadian study, SUNSET, mainly focuses on ultracentral lesions using SABR techniques.14, 15
With the full results of these prospective trials still unavailable, we aimed to clarify the effects of current treatment regimens and predisposing factors for increased toxicities in central lung cancers. In the current study, we identified patients treated in our center and reviewed their long-term outcomes regarding LC, OS, and toxicities after SABR for centrally located primary lung and oligometastatic tumors.
After approval by our institutional review board, we retrospectively searched our patient database for the records of all consecutive patients treated with their first SABR course to one or more centrally located lung lesions between October 2009 and April 2016 at our hospital. Primary stage I or II non-small cell lung cancers (NSCLCs), recurrent tumors after previous irradiation (regularly fractionated treatments), and oligometastatic tumors from other primary organs were included. Lesions were grouped according to distance from the tracheobronchial tree and mediastinum: 1) tumors with gross tumor volume (GTV) and/or planning target volume (PTV) very close to or abutting the tracheobronchial tree (≤ 1 cm); 2) tumors with GTV and/or PTV 1 to 2 cm away from the tracheobronchial tree; 3) tumors intersecting the mediastinum; and 4) tumors abutting the aorta. Patients with at least 3 months of follow-up, or patients who died within 3 months after SABR completion, were included in all of the analyses.
All patients were simulated in the supine position using a wing board. Patients had 1 of 3 motion management methods: 4-dimensional computed tomography (CT) using a Respiratory Gating System (Anzai Medical) or a Real-time Position Management System (Varian Medical Systems), CT performed during 3 phases (free breathing, end-expiratory phase, and inspiratory phase), or planning CT during free-breathing or during breath-hold. CT slice thickness was set at 1 to 1.5 mm. Positron emission tomography (PET)/CT fusion was used to assist delineation for some tumors. The target tumor (as GTV) was delineated on the maximum intensity projection when applicable or by using volumes from all 3 phases of breathing, which were united to form the internal target volume. No additional expansion was given to form the clinical target volume (i.e., clinical target volume equaled GTV). PTV margin was given as a 0.5 cm isotropic expansion to the internal target volume for all cases.
All patients were treated using a linear accelerator (Trilogy or TrueBeam STx; Varian Medical Systems). One patient had a tumor treated by CyberKnife (Accuray, Inc).
Organs-at-risk dose constraints and PTV coverage were done according to the RTOG study protocols. Kilovoltage portal imaging and cone beam CT were used in every fraction for every patient’s treatments during the daily setup. For the patient treated by CyberKnife, the Xsight lung tracking and Synchrony systems (Accuray, Inc) were used.
Treatment dose and fractionation were determined at the discretion of the treating physician, but lower doses or more protracted schedules, in general, were used for patients undergoing reirradiation and for tumors abutting the tracheobronchial tree. BED calculations, based on alpha/beta ratios of 10 (acute) and 3 (late) evaluations, were performed conventionally on the basis of classic radiobiology principles in radiation oncology.
Toxicity-free survival (TFS) and local relapse-free survival (LRFS) were calculated as time since the end of SABR to event occurrence (death or a grade 2 or higher toxicity for TFS and death or locoregional relapse for LRFS, whichever occurred earlier). OS for patients with multiple SABR treatments was calculated as time since the end of the last SABR to death. Toxicity was graded according to the Common Terminology Criteria for Adverse Events, 4th edition.
OS, TFS, and LRFS were calculated using the Kaplan-Meier method, and log-rank tests were used for comparison between groups.
Our search identified 65 patients (70 lesions) with at least 3 months of follow-up or who died within 3 months after SABR completion. The type of tumor was primary lung in 49 (70%) and oligometastatic in 21 (30%). The patient, tumor, and treatment characteristics are summarized in Table 1. The treatment planning was 4-dimensional CT in 15 patients (23%), CT during 3 phases in 43 (66%), and CT during free-breathing or during breath-hold in 7 (11%). PET/CT fusion was used to assist delineation for 50 patients (77%). Volumetric modulated arc therapy was the most commonly used technique (34, 52%), followed by 3-dimensional conformal (29, 45%) and dynamic conformal arc (2, 3%) radiotherapies. Median (range) total dose was 55 Gy (30–60 Gy), fraction dose was 9.75 Gy (4–18 Gy), BED10 was 110 Gy (41–151 Gy), and BED3 was 228 Gy (90–378 Gy). The median (range) number of fractions was 5 (3–10).
Patient, tumor, and treatment characteristics for 65 patients (70 tumors) receiving stereotactic ablative radiotherapy (SABR)
Characteristic | Value Values are median (range) or No. of patients/tumors (%). |
---|---|
Age, year | 64 (22 |
Men | 50 (77) |
Primary cancer | |
Lung | 49 (70) |
Colorectal | 10 (14) |
Other (breast, gastric, melanoma, germ cell, RCC) | 11 (16) |
Treatment indication | |
Primary lung (medically inoperable T1–T2) | 12 (17) |
Relapse (primary lung and oligometastatic) | 24 (34) |
Oligometastatic | 34 (49) |
Previous radiation to chest | 20 (29) |
Tumor location | |
≤ 1 cm from tracheobronchial tree | 24 (34) |
> 1 cm but ≤ 2 cm from tracheobronchial tree | 12 (17) |
Lesions intersecting mediastinum | 22 (31) |
≤ 1 cm from thoracic aorta | 12 (17) |
Left laterality | 37 (53) |
Lesion size (PTV), cc | 33.4 (7.3–461.5) |
Total dose, Gy | 55 (30–60) |
Dose per fraction, Gy | 9.75 (4–18) |
Fractions | 5 (3–10) |
BED10, Gy | 110 (48–151.2) |
BED10 | |
< 100 Gy | 16 (23) |
≥ 100 Gy | 54 (77) |
BED3, Gy | 228 (90–378) |
Treatment time, days | 10 (5–19) |
Treatment time | |
< 10 days | 30 (43) |
≥ 10 days | 40 (57) |
Treatment on consecutive days | 6 (9) |
BED = biological effective dose; PTV = planned tumor volume; RCC = renal cell carcinoma;
Reirradiation was performed for 20 tumors (28%) (Table 1). The median dose given as reirradiation was lower than for other tumors (reirradiation BED10 dose: 94.4 Gy reirradiation
After a median follow-up of 57 months (95% CI, 48–65 months), 43 (61%) of the tumors achieved complete response (Table 2). On univariate analysis, BED10 (> 100
Tumor and patient outcomes after stereotactic ablative radiotherapy (SABR) for central lung tumors
Characteristic | Value Values are No. patients/tumors (%) or No. patients unless otherwise stated. |
---|---|
Response on 3-month PET/CT after SABR | |
Complete response | 43 (61) |
Partial response | 19 (27) |
Progression | 2 (3) |
Unknown (patient died before 3 months or imaging not performed) | 6 (9) |
Locoregional control | |
2-year | 84% |
5-year | 70% |
Median | Not reached |
Overall survival | |
2-year | 52% |
5-year | 28% |
Median | 28 months |
2-Year toxicity-free survival | 81% |
All Toxicities (grade 2 or higher) | 17 (26.2%) |
RT-induced pneumonitis | 9 (13.8%) |
Brachial and recurrent laryngeal nerve injury | 3 (4.6%) |
Esophagitis | 2 (3%) |
Tracheal perforation | 1 (1.5%) |
Fatal hemoptysis | 1 (1.5%) |
Possible RT-related death | 1 (1.5%) |
Toxicity, grade 5 (fatal) | 5 (7.7%) |
RT-induced pneumonitis | 2 (3%) |
Tracheal perforation | 1 (1.5%) |
Fatal hemoptysis | 1 (1.5%) |
Possible RT-related death | 1 (1.5%) |
PET/CT = positron emission tomography/computed tomography; RT = radiotherapy;
LRFS was lower in patients with colorectal cancer as a primary tumor (2-year LRFS: colorectal metastases, 59%
During follow-up, 10 tumors (14%) relapsed (2-and 5-year LC were 84% and 70%, respectively), and 37 patients (57%) died (2- and 5-year OS were 52% and 28%, respectively). Median OS was significantly lower in patients who had toxicity of grade 3 or higher (5 months, grade ≥ 3 toxicity
Seventeen toxicities of grade 2 or higher were observed in 13 patients, some patients have more than 1 toxicity (Table 2). Imaging examples of patients with tracheal rupture and vocal cord paralysis are shown in Figure 3. The most common toxicity was radiation-induced pneumonia. Less common toxicities, including brachial plexus injury (giving rise to Lhermitte sign) and vocal cord paralysis (due to vagus or recurrent laryngeal nerve injury), were observed in 3 patients; radiation-related esophagitis occurred in 2 patients.
Seven of the 10 toxicities of grade 3 to 5 were observed in reirradiation patients, which conferred an HR of 5.8 (95% CI, 1.7–20.3). Also, 7 of 10 grade 3 to 5 toxicities were observed in lesions abutting the tracheobronchial tree, for an HR of 4.5 (95% CI, 1.3–15.8). Among the 17 toxicities, 5 were grade 5 (fatal). Three out of 5 fatal toxicity patients were reirradiated to the same RT field, and one of them was irradiated to a neighboring field. The prior and reirradiation doses of each patients were 66Gy/33 fractions and 30 Gy/5 fractions; 40 Gy/10 fractions and 59.5Gy/7 fractions; 66 Gy/33 fractions and 30 Gy/5 fractions; and 45 Gy/15 fractions with the neighboring field dose and 50 Gy/5 fractions, respectively. We were able to get the medical reports and the thoracic CT for 3 of the patients and confirmed the grade 5 toxicity; in regard to patient #4, which was reported as “possible RT-related death,” this was due to the fact that his death was unexpected, and happened only a few weeks shortly after his SABR course; this information was given to us by his relatives. To be estimating this toxicity rate conservatively, we believe that it is reasonable to account for this in the statistics (so it did not appear that we were biased), as the death did happen within one month after SABR. The last patient who had grade 5 toxicity after 1st SABR was treated to a totaldose of 59.5Gy in 7 fractions and notably he had a lesion encasing bronchus with a size of 55 mm which was considered to be a larger lesion for SABR. After a reasonable amount of effort, we could not locate his radiological images; however, the emergency medical notes noted symptoms and signs of him developing an acute pneumonia. As a result, we considered the possibility that it could be a RT-related pneumonia due to the proximity of timing to his SABR course.
Survival free of grade 3 to 5 toxicity was lower after reirradiation than in patients without reirradiation (2-year TFS: 63% after reirradiation
Grade 3 or higher complications of SABR for centrally located lung tumors are still a substantial concern, as reported by multiple studies, including the most recently published NRG Oncology/ RTOG 0813 trial.5,6,8,9,12 Therefore, more studies are required to evaluate whether these findings are similar in the general population. To our knowledge, the current retrospective study is one of the largest series to date for centrally located and ultra-central lung tumors. Favorable outcome and toxicity profiles were achieved, which supports the use of 5-fraction and also moderately hypofractionated regimens in this population.
The LC rates in our series are comparable to those of other published series which showed excellent tumor control. Although we saw no correlation of BED10 doses higher than 100 Gy with better LC, previous studies indicated that BED10 of 100 Gy or higher led to better local progression-free survival and OS.3, 4 The reason for the lack of correlation in our study may be the high number of reirradiation lesions, which were prescribed lower radiotherapy doses (mean reirradiation BED10 dose, 94.4 Gy). reirradiation lesions also had shorter follow-up, so their local recurrence rates may appear lower at the time of data analysis. The difference also may relate to the heterogeneity of these tumors, including colorectal oligometastatic, lung cancers with epidermal growth factor receptor or anaplastic large-cell lymphoma kinase–gene mutations, and other confounding factors such as chemotherapy before or after SABR. If only non-reirradiation primary lung lesions are considered, the LC rates in our study (2-year LC, 71%) are similar to those in the literature.2 Metastatic tumors with a separate primary seemed to have higher LC rates (2-year LC, 81%) than those reported in the literature (51%–96%, with various radiotherapy doses).1 At this time, there is no clear correlation between LC and radiotherapy doses, although LC was found to be positively correlated with favorable response radiographically 3 months after SABR by PET/CT in our study (the use of PET/CT for follow-up is a routine practice at our institution).
In our series, 2- and 5-year OS were 48% and 20%, respectively, for patients with primary lung cancer and were 60% and 44%, respectively, for patients with oligometastatic tumors. The 2-year OS rates in the literature range from 33% to 84% depending on primary tumor type, size and number of lesions, disease-free survival from primary tumor treatment to onset of metastasis, and other treatment-related factors.1 Similarly, survival after SABR for patients with NSCLC has also varied among studies, with 2-year OS ranging from 43% to 90% depending on radiotherapy dose, tumor size, clinical performance status, and tumor location (central
Compared with rates reported in the literature, a slightly higher rate of possible grade 5 toxicities was noted in our cohort; 5 patients who died had treatment complications that may have been causative, including pneumonitis, tracheal perforation, and hemoptysis. OS in patients with grade 3 to 5 toxicity was short, with a median of only 5 months after SABR. Reirradiation carried significant risks in these cases because it resulted in a high cumulative dose in the mediastinum. More guidance and research in the future are required for making SABR safer in these clinical scenarios, in which patients often have no other choice but reirradiation, along with proper counseling regarding potential treatment outcomes and adverse effects.
For centrally located lung tumors or nodal recurrences after previous irradiation, some authors have discouraged the use of SABR because of the perceived high risks of toxicity.16, 17 In other studies that included central lesions without prior radiotherapy, a higher rate of grade 5 toxicities was often reported.16, 17, 18 In an analysis of 32 lesions (11 central) that were previously irradiated, Peulen
The GTV or PTV was within 1 cm of the tracheobronchial tree (ultracentral) in 24 (34%) of our patients. Four of these patients had grade 5 toxicity. Because 3 of those patients also had reirradiation, we do not know conclusively whether the death was related to reirradiation, tumor proximity to the tracheobronchial tree, or both. The literature reports conflicting results regarding the importance of proximity to the tracheobronchial tree (lesions abutting the tracheobronchial tree
Vocal cord paralysis is a rarely recognized complication of SABR. To our knowledge, only 2 studies have reported its occurrence.19, 20 Shultz
Our study has several limitations. The study was retrospective, and the patient population was more heterogeneous than in other reported series on this topic (in terms of radiotherapy dose and also inclusion of primary lung
SABR is an effective treatment modality for centrally located lung cancers. SABR to reirradiation lesions, and possibly lesions abutting the tracheo-bronchial tree, appeared to carry a higher risk of higher grade toxicities developing in the long term. More research is needed to define the optimal dose and fractionation schedule for both centrally and ultracentrally located lung tumors. We are waiting for completion of more prospective trials, which will hopefully give more information regarding suitable treatment regimens and clearer factors that may predispose patients to increased toxicities after SABR for central lung cancers.