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Outcome of four-dimensional stereotactic radiotherapy for centrally located lung tumors
Radiotherapy and Oncology 102 (2012) 383–387
Contents lists available at SciVerse ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
SBRT in lung cancer
Outcome of four-dimensional stereotactic radiotherapy for centrally located lung tumors q Joost J. Nuyttens a,⇑, Noelle C. van der Voort van Zyp a, John Praag a, Shafak Aluwini a, Rob J. van Klaveren b, Cornelis Verhoef d, Peter M. Pattynama c, Mischa S. Hoogeman a a
Department of Radiation Oncology; b Department of Pulmonology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; c Department of Radiology, Groene Hart Ziekenhuis, Gouda, The Netherlands; d Department of Surgical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 8 July 2011 Received in revised form 14 December 2011 Accepted 23 December 2011 Available online 20 January 2012 Keywords: Stereotactic radiotherapy Lung cancer Central tumors Real-time tumor tracking
a b s t r a c t Purpose: To assess local control, overall survival, and toxicity of four-dimensional, risk-adapted stereotactic body radiotherapy (SBRT) delivered while tracking respiratory motion in patients with primary and metastatic lung cancer located in the central chest. Methods: Fifty-eight central lesions of 56 patients (39 with primary, 17 with metastatic tumors) were treated. Fifteen tumors located near the esophagus were treated with 6 fractions of 8 Gy. Other tumors were treated according to the following dose escalation scheme: 5 fractions of 9 Gy (n = 6), then 5 fractions of 10 Gy (n = 15), and finally 5 fractions of 12 Gy (n = 22). Results: Dose constraints for critical structures were generally achieved; in 21 patients the coverage of the PTV was reduced below 95% to protect adjacent organs at risk. At a median follow-up of 23 months, the actuarial 2-years local tumor control was 85% for tumors treated with a BED >100 Gy compared to 60% for tumors treated with a BED 6100 Gy. No grade 4 or 5 toxicity was observed. Acute grade 1–2 esophagitis was observed in 11% of patients. Conclusion: SBRT of central lung lesions can be safely delivered, with promising early tumor control in patients many of whom have severe comorbid conditions. Ó 2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 102 (2012) 383–387
Stereotactic body radiotherapy (SBRT) targets and delivers high, ablative doses of radiation to sites within the body while applying methods to reduce the effects of tumor motion to help assure accuracy and precision. SBRT has resulted in high local tumor control rates for early-stage non-small cell lung cancer (NSCLC) patients with peripheral tumors [1–3]. Considering the high local control with the low toxicity, withholding SBRT from patients with stage I NSCLC who are elderly with COPD is not routinely justified [4,5]. Less experience exists in SBRT for central lung tumors because they are relatively rare and because common SBRT dosing schedules, such 3 fractions of 20 Gy, cannot be safely used due to the proximity of trachea, mainstem bronchus, esophagus or heart. Serious complications, including death following bacterial pneumonia, pericardial effusion, radiation pneumonitis, or massive hemoptysis, have been reported [6,7]. By increasing the number of fractions and reducing the fractional dose, some
q Presented at the 29th ESTRO 2010 by Joost J. Nuyttens and rewarded with the ESTRO-ACCURAY Award. ⇑ Corresponding author. Address: Department of Radiation Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Postbus 2040, 3000 CA Rotterdam, The Netherlands. E-mail address: [email protected] (J.J. Nuyttens).
0167-8140/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2011.12.023
groups have reported successful treatment of central lung tumors with minimal complications [1]. However, some authors did report grade 5 toxicity related to the stereotactic radiotherapy treatment [6,8–10]. We have found that 4D SBRT, in which 3D dose distributions track the tumor as it moves with respiration, allows significant dose escalation without increasing the dose to normal tissue relative to conventional 3D CRT that does not track respiratory motion [11]. In our early experience treating patients with inoperable stage I NSCLC, the actuarial 2-year local control rate for patients treated with 60 Gy was 96% at a median follow-up of 15 months and overall survival for the whole group at two years was 62%. Late grade 3 toxicity, including radiation pneumonitis and thoracic pain, was observed in 10% of the patients, but no grade 4 or higher toxicity occurred. More recently we reported that quality of life can be maintained or improved after 4D SBRT for patients with central tumors [12], even elderly patients [5], provided the fractional dose, number of fractions, and dose distribution are adapted to the risk of injury to central structures. From July 2006 until September 2009, we treated 56 patients with 58 centrally located tumors in the lung or mediastinum. In this report we focus on these central lung tumors, examining local tumor control, survival and toxicity after treatment using respiratory real-time tumor tracking.
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Stereotactic radiotherapy for tumors central in the lung
Methods and materials Fifty-eight central tumors in 56 patients were treated with the respiratory tumor tracking system of the CyberKnife including early stage non-small cell lung cancer (n = 39) and solitary metastases (n = 17). These patients were not eligible for surgery or chemotherapy due to their comorbidity (50 patients), refused surgery or chemotherapy (3 patients), or had an inoperable tumor (3 patients). The patient characteristics are shown in Table 1. The study was not submitted to an institutional ethics committee. Central tumors included (1) 52 tumors located <2 cm from the trachea, mainstem bronchus, main bronchi or esophagus, (2) 3 tumors located <6 mm from the heart and (3) 3 tumors located in the mediastinum. The median tumor size was 4.1 cm (range: 1.2– 10.5 cm). Fifteen tumors located near the esophagus were treated with 6 fractions of 8 Gy. Using this schedule, the maximum dose constraint for the esophagus was 6 Gy/fraction, for the trachea and mainstem bronchus 8 Gy/fraction, and for the spinal cord 4.5 Gy/fraction. However, 0.5 cm3 of these organs at risk were allowed to get a higher dose than set by the constraint. All other central tumors (close to the mainstem bronchus but not the esophagus) were initially treated with 5 fractions of 9 Gy (n = 6). This dose was subsequently escalated to 5 fractions of 10 Gy (n = 15) and later to 5 fractions of 12 Gy (n = 22). Using the 5 fractions/12 Gy schedule, the maximum dose constraint for the esophagus was 7 Gy/fraction, for the trachea 10 Gy/fraction, for the mainstem bronchus 12 Gy/fraction, and for the spinal cord 5.5 Gy/fraction. However, 0.5 cm3 of these organs at risk were allowed to get a higher dose than the set by constraint. The planning target volume (PTV) equaled gross tumor volume (GTV) plus 5 mm. The median volume of the GTV and PTV was 34 and 70 cm3, respectively (GTV, range: 1–377 cm3 and PTV: range, 6–535 cm3). The dose to the PTV was prescribed to the 75–90% isodose line (median 80%), covering at least 95% of the PTV. However, in order to respect the constraints of the organs at risk, an underdosage of the PTV was allowed. Tissue density correction was performed by using the equivalent path method.
The median follow up was 23 months (range: 1–54 months). The median age was 73 years (range: 34–88 years). In total, 181 fiducials were placed in all patients using 5 different methods: (1) the intravascular method was used to place 122 fiducials in 38 tumors (36 patients) (2) the percutaneous intrapulmonary method was used to place 43 fiducials in 16 tumors (16 patients), (3) the percutaneous extrapulmonary approach was used to place 9 fiducials against the ribs or sternum to mark 2 fixed tumors to the chest wall or mediastinum (2 patients), (4) bronchoscopy was used to place 4 fiducials in 1 tumor (1 patient), and (5) endoscopic ultrasound was used to place 3 fiducials in 1 tumor (1 patient). To compare the dose at the organs at risk across the various fractionation schemes, all treatment schedules were converted into an equivalent dose of 2 Gy (EQD2) and a Biological Equivalent Dose (BED). The following formulas were used to convert the dose: EQD2 = Dx(d + a/b)/(2.0 + a/b), and BED = Dx(1+(d/ (a/b)) with D = total dose, d = dose per fraction and a/b = 3 Gy for organs at risk (OAR) and a/b = 10 Gy for tumor. Local control (LC) was calculated from the first day of treatment until the diagnosis of a local recurrence. Patients without a local recurrence were censored on the last day of contact. In the absence of biopsy confirming viable carcinoma, local recurrence was defined as a 20% increased tumor dimension on the CT-scan compared to the previous CT-scan. In addition a corresponding avid lesion on the PET-scan was required. Overall survival (OS) was measured from the start of radiotherapy until death from any cause. Patients still alive at the date of last contact were censored. The primary objective of the study was to evaluate the efficacy of radiotherapy in terms of local control. The secondary endpoint was overall survival and toxicity. LC and OS were estimated by the Kaplan–Meier method, and 95% confidence intervals (CIs) were constructed. Kaplan–Meier curves were generated to illustrate the differences between subgroups and compared using the log-rank test. All reported P-values are two-sided and a significance level a = 0.05 was used. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events version 3.0.
Results Table 1 Patient characteristics. Median age (years, range)
73 (34–88)
Charlson comorbidity score >4 3–4 1–2 0
16 (29%) 17 (30%) 19 (34%) 4 (7%)
Cumulative illness score >6 5–6 0–4
10 (18%) 19 (34%) 27 (48%)
Histology of early stage lung ca Large cell carcinoma Squamous cell carcinoma Adenocarcinoma Undifferentiated carcinoma No biopsy or inconclusive biopsy
23 (59%) 9 (23%) 9 (23%) 4 (10%) 1 (3%) 16 (41%)
Primary tumors of the metastasis Colorectal cancer Lung cancer Other
10 (59%) 2 (12%) 5 (29%)
Gross tumor volume (cm3) Median (range)
34 (1–377)
Planned tumor volume (cm3) Median (range)
70 (6–535)
Tumor diameter (cm) Median (range)
4.1 (1.2–10.5)
The median coverage of the GTV with the prescription dose was 100% (range, 77–100%). In 13 tumors, the coverage of the GTV was below 99%. The median coverage of the PTV with the prescription dose was 97% (range, 55–100%). In 21 tumors (36%), the coverage of the PTV was below 95%. The median PTV volume receiving less than 95% of the prescribed dose was 2.4 cm3 (range, 0–120 cm3). Dosimetric characteristics of the organs at risk receiving EQD2 of more than 65 Gy or a BED of more than 110 are shown in Table 2. The median volume of the main bronchi irradiated to an EQD2 of 130 Gy or a BED of 216 Gy in 29 patients was 0.4 cm3 (range, 0.001–4.9 cm3). The median volume of the myelum irradiated to an EQD2 of 50 Gy or a BED of 82 Gy in 9 patients was 0.02 cm3 (range, 0.002–0.9 cm3). For the whole group, local tumor control was 91% at one year and 76% at two years. The actuarial 2-year local tumor control was 85% for tumors treated with a dose >50 Gy (BED > 100 Gy) compared to 60% for tumors treated with 650 Gy (BED 6 100 Gy) (p = 0.10, Fig. 1A). Eleven local recurrences occurred in ten patients after treatment with 45 Gy in 5 fractions (n = 2), 48 Gy in 6 fractions (n = 4), and 60 Gy in 5 fractions (n = 5). The local tumor control rate at two years was better in patients with early stage lung cancer than patients with lung metastasis: 85% versus 64% (p = 0.21, Fig. 1B). The actuarial overall survival for the whole group was 60% at 2 years and 50% at 3 years. The actuarial overall survival at 2 years was 53% in patients with early stage lung cancer and 75% in patients
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J.J. Nuyttens et al. / Radiotherapy and Oncology 102 (2012) 383–387 Table 2 Dosimetric characteristics of the organs at risk receiving more than 65 Gy3 (EQD2) or 110 BED.
Main bronchi Trachea Esophagus Plexus brachialis
Median Dmax in EQD2 (range)
Median Dmax in BED (range)
Median V65 in cm3 (range)
Number of patients
148 (78–236) 101 (83–131) 88 (68–112) 83 (73–90)
246 168 143 140
2.1 (0.01–13.8) 1.1 (0.01–7.4) 0.3 (0.002–4.7) 0.09 (0.02–0.2)
43 9 18 4
(130–394) (139–219) (112–188) (122–150)
with lung metastasis (p = 0.56, Fig. 2). Twenty-seven patients died: 13 due to tumor progression and 14 due to comorbid disease. The 3year cancer-specific survival was 80% for early stage lung cancer patients, compared to 58% for patients with lung metastases. No acute or late grade 4 or 5 toxicity was recorded. The acute and late complications are shown in Table 3. The cause of the acute grade 3 pneumonitis was probably exacerbation of COPD, but could have been related to the radiotherapy treatment. Two patients (4%) with large PTVs (>150 cm3) were diagnosed with rib fractures. The rib fractures were diagnosed 12 months after the treatment or later, and one of the patients did not report pain from the rib fractures. In 3 patients, the late grade 3 pneumonitis was clearly related to the radiotherapy, in the other patients it also could have been exacerbations of COPD. No correlation between toxicity, tumor location and dose to critical organs could be found.
Discussion The tumor-ablative effects of high-dose SBRT for lung cancer can be safely extended to lesions in the central chest if treatment is adapted to reduce the risk of OAR injury. Several studies have now shown that delivering lower doses over 4–10 fractions can reduce toxicity of SBRT in the central chest [10,13–18], although doses that are often used in treating peripheral lung lesions can result in serious toxicity and death when delivered to central lesions [6,7,9,19], or can result in at least a higher rate of toxicity than for peripheral lesions [8]. The published studies to date have typically consisted of a mixed population of peripheral and central tumors and included relatively small number of patients (8–27 patients) with central tumors. In some studies in which lower fraction doses were delivered, reduced toxicity seemed to come at the expense of poorer local control. For example, Taremi et al. delivered 50 Gy or 60 Gy in 8 fractions to 20 patients with central lesions (out of 108 patients treated overall), and observed no severe toxicity related to tumor
location [17]. However, seven of the 10 local recurrences were central lesions, five of which were treated with 50 Gy. Chang et al. observed low toxicity but a high recurrence rate (43%) in 7 patients treated to 40 Gy in 4 fractions [14]. A similar combination of low dose (BED < 100 Gy) with relatively low toxicity and relatively low local control was obtained by Onimaru et al. [10] and Guckenberger et al. [20]. We treated several of our patients with doses lower than 50 Gy, and found a statistical trend toward poorer tumor control in these patients, a finding that is consistent with these reports. Other authors, however, have reported the ability to deliver doses equal to or above BED = 100 Gy, resulting in the combination of good tumor control (>85% at 1.5–2 years) and low toxicity [15,16,18]. Stephans et al. for example, were able to treat central lung lesions without serious toxicity either using 50 Gy delivered in 5 fractions. Patients were immobilized in a stereotactic frame and abdominal compression was applied to reduce tumor motion. Tumor control at a median follow-up of 18.4 months was 98%. We were also able to deliver doses above BED = 100 Gy, and as previously noted obtained superior disease control relative to lower doses. However, Takeda et al. found a significant lower local control after SBRT with 50 Gy in 5 fractions in patients with oligometastatic tumors from colorectal cancer compared to patients with primary lung cancer (2-year local control rates of 73% compared to 95%) [21]. Thus, we have a highly mixed scenario in the literature: high central doses are often correlated with high toxicity and good tumor control, and low doses are often correlated with low toxicity and poor tumor control. But in some reports high doses were shown to be safely delivered and lower doses have yielded good tumor control. It is not clear how these studies differ, but there are differences in the definition of ‘‘central’’ lesions. Exclusions of lesions too near critical structures such as the hilum and the esophagus may have resulted in differences in patient selection that magnified or allayed toxicity concerns. For example, Stephans et al. delivered a lower dose, 50 Gy in 10 fractions, to 6 patients with large-volume tumors adjacent to critical structures, but these
Fig. 1. (A) Local control according to dose. (B) Local control for early stage lung cancer and lung metastases.
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Stereotactic radiotherapy for tumors central in the lung
Fig. 2. Overall survival for metastatic patients and patients with early stage lung cancer.
patients were excluded from their report; they reported outcomes only for the 7 patients who received 50 Gy in 5 fractions, who presumably did not have lesions adjacent to critical structures. Another reason for this difference in local control and toxicity could be the dose coverage of the PTV and GTV. In 36% of the tumors, we underdosed the PTV to avoid toxicity. This information is not given in the other published articles on central tumor treatment. Underdosage to the PTV and GTV could be a cause of higher local failure, but this was not a statistically significant effect in our population. Some authors have reported low toxicity [15,16,18]. However five other publications report death due to pulmonal complications and two due to esophageal complications. Two authors [8,19] reported the death of one patient secondary to bronchial stenosis and subsequent bleeding from the bronchus. In one patient, the dose to the tumor was 48 Gy in 4 fractions, in the other patient the dose was not specified (but was probably 60 Gy in 4 fractions, based on other details in the report). Milano et al. reported one death due to fatal hemoptysis after treatment of a mediastinal mass abutting the bronchus [22]. The cumulative dose to the bronchus was 98 Gy. Le et al. reported 2 deaths due to pulmonary complications [6]. Both patients were treated previously with radiotherapy to the chest. Fakaris et al. reported five grade 5 toxicities, all possibly related to the stereotactic treatment of 22 patients, and three of them due to pneumonia, one to hemoptysis and one to respiratory failure [9]. Le et al reported the death of one patient due to esophageal fistula followed by a fatal hemoptysis from a tracheovascular fistula. Brachial plexopathy has been reported in 2 patients: one patient developed a brachial plexopathy that was managed medically, however, the dose to the plexus was not reported [13]. The other one developed brachial plexus neuropathy and partial arm paralysis after receiving a dose of 40 Gy (in 4 fractions) to a significant volume of the plexus [14]. Table 3 Acute and late complications (number of patients). Acute complications
Esophagitis Thoracic pain Pneumonitis
Late complications
Grade 1
Grade 2
Grade 3
Grade 1
Grade 2
Grade 3
6 2 11
4 1 6
0 0 4
2 2 4
0 4 7
0 0 6
In the present study of 58 patients, toxicity rates were among the lowest reported to date at all doses delivered, although the medium maximum dose to the main bronchi was 146 Gy3 and 88 Gy3 for the esophagus. This information has not been reported in previous published articles. We believe that risk-adapted treatment of central lesions requires both a consideration of the maximum overall and fraction doses and care to optimize the dose distribution to meet strict dose constraints for sensitive central structures, because several authors did report grades 4 and 5 toxicity. The fact that even doses as low of 40 Gy can cause significant complications points to the critical importance of careful treatment planning, accurate patient setup, and precise radiation delivery throughout a treatment fraction [19]. Toward this goal we have benefited greatly from the ability to use small margins of 5 mm around the GTV. The small margins could be achieved by the use of in-room inter-fraction and intra-fraction tumor motion compensation by the respiratory tracking system. For this system, a targeting error of less than 1.5 mm was achieved routinely [23–25]. Using this method, 2-year tumor control and overall survival have been comparable to that generally reported for SBRT of peripheral NSCLC lesions for patients treated to BED = 100 Gy, and toxicity has been among the lowest reported for central lesions. Conclusion Four-dimensional lung tumor tracking is feasible for central tumors. The local tumor control rate was 76% at two years. Local tumor control was better in patients with early stage lung cancer compared to patients with metastasis. The actuarial overall survival at 2 years was 54% in patients with early stage lung cancer and 75% in patients with lung metastasis. Esophagus toxicity was low when applying a maximum EQD2 constraint of 65 Gy or a maximum BED of 82 Gy. References [1] Chi A, Liao Z, Nguyen NP, Xu J, Stea B, Komaki R. Systemic review of the patterns of failure following stereotactic body radiation therapy in early-stage nonsmall-cell lung cancer: clinical implications. Radiother Oncol 2010;94:1–11. [2] Andratschke N, Zimmermann F, Boehm E, et al. Stereotactic radiotherapy of histologically proven inoperable stage I non-small cell lung cancer: patterns of failure. Radiother Oncol 2011;101:245–9. [3] Nath SK, Sandhu AP, Kim D, et al. Locoregional and distant failure following image-guided stereotactic body radiation for early-stage primary lung cancer. Radiother Oncol 2011;99:12–7. [4] Louie AV, Rodrigues G, Hannouf M, et al. Withholding stereotactic radiotherapy in elderly patients with stage I non-small cell lung cancer and co-existing COPD is not justified: outcomes of a Markov model analysis. Radiother Oncol 2011;99:161–5. [5] van der Voort van Zyp NC, van der Holt B, van Klaveren RJ, Pattynama P, Maat A, Nuyttens JJ. Stereotactic body radiotherapy using real-time tumor tracking in octogenarians with non-small cell lung cancer. Lung Cancer 2010;69:296–301. [6] Le QT, Loo BW, Ho A, et al. Results of a phase I dose-escalation study using single-fraction stereotactic radiotherapy for lung tumors. J Thorac Oncol 2006;1:802–9. [7] Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 2006;24:4833–9. [8] Bral S, Gevaert T, Linthout N, et al. Prospective, risk-adapted strategy of stereotactic body radiotherapy for early-stage non-small-cell lung cancer: results of a phase II trial. Int J Radiat Oncol Biol Phys 2011;80:1343–9. [9] Fakiris AJ, McGarry RC, Yiannoutsos CT, et al. Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study. Int J Radiat Oncol Biol Phys 2009;75:677–82. [10] Onimaru R, Shirato H, Shimizu S, et al. Tolerance of organs at risk in smallvolume, hypofractionated, image-guided radiotherapy for primary and metastatic lung cancers. Int J Radiat Oncol Biol Phys 2003;56:126–35. [11] Prevost JB, Voet P, Hoogeman M, Praag J, Levendag P, Nuyttens JJ. Fourdimensional stereotactic radiotherapy for early stage non-small cell lung cancer: a comparative planning study. Technol Cancer Res Treat 2008;7:27–34. [12] van der Voort van Zyp NC, Prevost JB, van der Holt B, et al. Quality of life after stereotactic radiotherapy for stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2010;77:31–7.
J.J. Nuyttens et al. / Radiotherapy and Oncology 102 (2012) 383–387 [13] Bradley JD, El Naqa I, Drzymala RE, Trovo M, Jones G, Denning MD. Stereotactic body radiation therapy for early-stage non-small-cell lung cancer: the pattern of failure is distant. Int J Radiat Oncol Biol Phys 2010;77:1146–50. [14] Chang JY, Balter PA, Dong L, et al. Stereotactic body radiation therapy in centrally and superiorly located stage I or isolated recurrent non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2008;72:967–71. [15] Lagerwaard FJ, Haasbeek CJ, Smit EF, Slotman BJ, Senan S. Outcomes of riskadapted fractionated stereotactic radiotherapy for stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2008;70:685–92. [16] Stephans KL, Djemil T, Reddy CA, et al. Comprehensive analysis of pulmonary function test (PFT) changes after stereotactic body radiotherapy (SBRT) for stage I lung cancer in medically inoperable patients. J Thorac Oncol 2009;4:838–44. [17] Taremi M, Hope A, Dahele M, et al. Stereotactic body radiotherapy for medically inoperable lung cancer: prospective, single-center study of 108 consecutive patients. Int J Radiat Oncol Biol Phys 2012;82:967–73. [18] Xia T, Li H, Sun Q, et al. Promising clinical outcome of stereotactic body radiation therapy for patients with inoperable Stage I/II non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2006;66:117–25. [19] Song SY, Choi W, Shin SS, et al. Fractionated stereotactic body radiation therapy for medically inoperable stage I lung cancer adjacent to central large bronchus. Lung Cancer 2009;66:89–93.
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[20] Guckenberger M, Wulf J, Mueller G, et al. Dose-response relationship for image-guided stereotactic body radiotherapy of pulmonary tumors: relevance of 4D dose calculation. Int J Radiat Oncol Biol Phys 2009;74:47–54. [21] Takeda A, Kunieda E, Ohashi T, Aoki Y, Koike N, Takeda T. Stereotactic body radiotherapy (SBRT) for oligometastatic lung tumors from colorectal cancer and other primary cancers in comparison with primary lung cancer. Radiother Oncol 2011;101:255–9. [22] Milano MT, Chen Y, Katz AW, Philip A, Schell MC, Okunieff P. Central thoracic lesions treated with hypofractionated stereotactic body radiotherapy. Radiother Oncol 2009;91:301–6. [23] Hoogeman M, Prevost JB, Nuyttens J, Poll J, Levendag P, Heijmen B. Clinical accuracy of the respiratory tumor tracking system of the cyberknife: assessment by analysis of log files. Int J Radiat Oncol Biol Phys 2009;74:297–303. [24] Muacevic A, Drexler C, Wowra B, et al. Technical description, phantom accuracy, and clinical feasibility for single-session lung radiosurgery using robotic image-guided real-time respiratory tumor tracking. Technol Cancer Res Treat 2007;6:321–8. [25] Seppenwoolde Y, Berbeco RI, Nishioka S, Shirato H, Heijmen B. Accuracy of tumor motion compensation algorithm from a robotic respiratory tracking system: a simulation study. Med Phys 2007;34:2774–84.
Contents lists available at SciVerse ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
SBRT in lung cancer
Outcome of four-dimensional stereotactic radiotherapy for centrally located lung tumors q Joost J. Nuyttens a,⇑, Noelle C. van der Voort van Zyp a, John Praag a, Shafak Aluwini a, Rob J. van Klaveren b, Cornelis Verhoef d, Peter M. Pattynama c, Mischa S. Hoogeman a a
Department of Radiation Oncology; b Department of Pulmonology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands; c Department of Radiology, Groene Hart Ziekenhuis, Gouda, The Netherlands; d Department of Surgical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, The Netherlands
a r t i c l e
i n f o
Article history: Received 8 July 2011 Received in revised form 14 December 2011 Accepted 23 December 2011 Available online 20 January 2012 Keywords: Stereotactic radiotherapy Lung cancer Central tumors Real-time tumor tracking
a b s t r a c t Purpose: To assess local control, overall survival, and toxicity of four-dimensional, risk-adapted stereotactic body radiotherapy (SBRT) delivered while tracking respiratory motion in patients with primary and metastatic lung cancer located in the central chest. Methods: Fifty-eight central lesions of 56 patients (39 with primary, 17 with metastatic tumors) were treated. Fifteen tumors located near the esophagus were treated with 6 fractions of 8 Gy. Other tumors were treated according to the following dose escalation scheme: 5 fractions of 9 Gy (n = 6), then 5 fractions of 10 Gy (n = 15), and finally 5 fractions of 12 Gy (n = 22). Results: Dose constraints for critical structures were generally achieved; in 21 patients the coverage of the PTV was reduced below 95% to protect adjacent organs at risk. At a median follow-up of 23 months, the actuarial 2-years local tumor control was 85% for tumors treated with a BED >100 Gy compared to 60% for tumors treated with a BED 6100 Gy. No grade 4 or 5 toxicity was observed. Acute grade 1–2 esophagitis was observed in 11% of patients. Conclusion: SBRT of central lung lesions can be safely delivered, with promising early tumor control in patients many of whom have severe comorbid conditions. Ó 2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 102 (2012) 383–387
Stereotactic body radiotherapy (SBRT) targets and delivers high, ablative doses of radiation to sites within the body while applying methods to reduce the effects of tumor motion to help assure accuracy and precision. SBRT has resulted in high local tumor control rates for early-stage non-small cell lung cancer (NSCLC) patients with peripheral tumors [1–3]. Considering the high local control with the low toxicity, withholding SBRT from patients with stage I NSCLC who are elderly with COPD is not routinely justified [4,5]. Less experience exists in SBRT for central lung tumors because they are relatively rare and because common SBRT dosing schedules, such 3 fractions of 20 Gy, cannot be safely used due to the proximity of trachea, mainstem bronchus, esophagus or heart. Serious complications, including death following bacterial pneumonia, pericardial effusion, radiation pneumonitis, or massive hemoptysis, have been reported [6,7]. By increasing the number of fractions and reducing the fractional dose, some
q Presented at the 29th ESTRO 2010 by Joost J. Nuyttens and rewarded with the ESTRO-ACCURAY Award. ⇑ Corresponding author. Address: Department of Radiation Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Postbus 2040, 3000 CA Rotterdam, The Netherlands. E-mail address: [email protected] (J.J. Nuyttens).
0167-8140/$ - see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2011.12.023
groups have reported successful treatment of central lung tumors with minimal complications [1]. However, some authors did report grade 5 toxicity related to the stereotactic radiotherapy treatment [6,8–10]. We have found that 4D SBRT, in which 3D dose distributions track the tumor as it moves with respiration, allows significant dose escalation without increasing the dose to normal tissue relative to conventional 3D CRT that does not track respiratory motion [11]. In our early experience treating patients with inoperable stage I NSCLC, the actuarial 2-year local control rate for patients treated with 60 Gy was 96% at a median follow-up of 15 months and overall survival for the whole group at two years was 62%. Late grade 3 toxicity, including radiation pneumonitis and thoracic pain, was observed in 10% of the patients, but no grade 4 or higher toxicity occurred. More recently we reported that quality of life can be maintained or improved after 4D SBRT for patients with central tumors [12], even elderly patients [5], provided the fractional dose, number of fractions, and dose distribution are adapted to the risk of injury to central structures. From July 2006 until September 2009, we treated 56 patients with 58 centrally located tumors in the lung or mediastinum. In this report we focus on these central lung tumors, examining local tumor control, survival and toxicity after treatment using respiratory real-time tumor tracking.
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Stereotactic radiotherapy for tumors central in the lung
Methods and materials Fifty-eight central tumors in 56 patients were treated with the respiratory tumor tracking system of the CyberKnife including early stage non-small cell lung cancer (n = 39) and solitary metastases (n = 17). These patients were not eligible for surgery or chemotherapy due to their comorbidity (50 patients), refused surgery or chemotherapy (3 patients), or had an inoperable tumor (3 patients). The patient characteristics are shown in Table 1. The study was not submitted to an institutional ethics committee. Central tumors included (1) 52 tumors located <2 cm from the trachea, mainstem bronchus, main bronchi or esophagus, (2) 3 tumors located <6 mm from the heart and (3) 3 tumors located in the mediastinum. The median tumor size was 4.1 cm (range: 1.2– 10.5 cm). Fifteen tumors located near the esophagus were treated with 6 fractions of 8 Gy. Using this schedule, the maximum dose constraint for the esophagus was 6 Gy/fraction, for the trachea and mainstem bronchus 8 Gy/fraction, and for the spinal cord 4.5 Gy/fraction. However, 0.5 cm3 of these organs at risk were allowed to get a higher dose than set by the constraint. All other central tumors (close to the mainstem bronchus but not the esophagus) were initially treated with 5 fractions of 9 Gy (n = 6). This dose was subsequently escalated to 5 fractions of 10 Gy (n = 15) and later to 5 fractions of 12 Gy (n = 22). Using the 5 fractions/12 Gy schedule, the maximum dose constraint for the esophagus was 7 Gy/fraction, for the trachea 10 Gy/fraction, for the mainstem bronchus 12 Gy/fraction, and for the spinal cord 5.5 Gy/fraction. However, 0.5 cm3 of these organs at risk were allowed to get a higher dose than the set by constraint. The planning target volume (PTV) equaled gross tumor volume (GTV) plus 5 mm. The median volume of the GTV and PTV was 34 and 70 cm3, respectively (GTV, range: 1–377 cm3 and PTV: range, 6–535 cm3). The dose to the PTV was prescribed to the 75–90% isodose line (median 80%), covering at least 95% of the PTV. However, in order to respect the constraints of the organs at risk, an underdosage of the PTV was allowed. Tissue density correction was performed by using the equivalent path method.
The median follow up was 23 months (range: 1–54 months). The median age was 73 years (range: 34–88 years). In total, 181 fiducials were placed in all patients using 5 different methods: (1) the intravascular method was used to place 122 fiducials in 38 tumors (36 patients) (2) the percutaneous intrapulmonary method was used to place 43 fiducials in 16 tumors (16 patients), (3) the percutaneous extrapulmonary approach was used to place 9 fiducials against the ribs or sternum to mark 2 fixed tumors to the chest wall or mediastinum (2 patients), (4) bronchoscopy was used to place 4 fiducials in 1 tumor (1 patient), and (5) endoscopic ultrasound was used to place 3 fiducials in 1 tumor (1 patient). To compare the dose at the organs at risk across the various fractionation schemes, all treatment schedules were converted into an equivalent dose of 2 Gy (EQD2) and a Biological Equivalent Dose (BED). The following formulas were used to convert the dose: EQD2 = Dx(d + a/b)/(2.0 + a/b), and BED = Dx(1+(d/ (a/b)) with D = total dose, d = dose per fraction and a/b = 3 Gy for organs at risk (OAR) and a/b = 10 Gy for tumor. Local control (LC) was calculated from the first day of treatment until the diagnosis of a local recurrence. Patients without a local recurrence were censored on the last day of contact. In the absence of biopsy confirming viable carcinoma, local recurrence was defined as a 20% increased tumor dimension on the CT-scan compared to the previous CT-scan. In addition a corresponding avid lesion on the PET-scan was required. Overall survival (OS) was measured from the start of radiotherapy until death from any cause. Patients still alive at the date of last contact were censored. The primary objective of the study was to evaluate the efficacy of radiotherapy in terms of local control. The secondary endpoint was overall survival and toxicity. LC and OS were estimated by the Kaplan–Meier method, and 95% confidence intervals (CIs) were constructed. Kaplan–Meier curves were generated to illustrate the differences between subgroups and compared using the log-rank test. All reported P-values are two-sided and a significance level a = 0.05 was used. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events version 3.0.
Results Table 1 Patient characteristics. Median age (years, range)
73 (34–88)
Charlson comorbidity score >4 3–4 1–2 0
16 (29%) 17 (30%) 19 (34%) 4 (7%)
Cumulative illness score >6 5–6 0–4
10 (18%) 19 (34%) 27 (48%)
Histology of early stage lung ca Large cell carcinoma Squamous cell carcinoma Adenocarcinoma Undifferentiated carcinoma No biopsy or inconclusive biopsy
23 (59%) 9 (23%) 9 (23%) 4 (10%) 1 (3%) 16 (41%)
Primary tumors of the metastasis Colorectal cancer Lung cancer Other
10 (59%) 2 (12%) 5 (29%)
Gross tumor volume (cm3) Median (range)
34 (1–377)
Planned tumor volume (cm3) Median (range)
70 (6–535)
Tumor diameter (cm) Median (range)
4.1 (1.2–10.5)
The median coverage of the GTV with the prescription dose was 100% (range, 77–100%). In 13 tumors, the coverage of the GTV was below 99%. The median coverage of the PTV with the prescription dose was 97% (range, 55–100%). In 21 tumors (36%), the coverage of the PTV was below 95%. The median PTV volume receiving less than 95% of the prescribed dose was 2.4 cm3 (range, 0–120 cm3). Dosimetric characteristics of the organs at risk receiving EQD2 of more than 65 Gy or a BED of more than 110 are shown in Table 2. The median volume of the main bronchi irradiated to an EQD2 of 130 Gy or a BED of 216 Gy in 29 patients was 0.4 cm3 (range, 0.001–4.9 cm3). The median volume of the myelum irradiated to an EQD2 of 50 Gy or a BED of 82 Gy in 9 patients was 0.02 cm3 (range, 0.002–0.9 cm3). For the whole group, local tumor control was 91% at one year and 76% at two years. The actuarial 2-year local tumor control was 85% for tumors treated with a dose >50 Gy (BED > 100 Gy) compared to 60% for tumors treated with 650 Gy (BED 6 100 Gy) (p = 0.10, Fig. 1A). Eleven local recurrences occurred in ten patients after treatment with 45 Gy in 5 fractions (n = 2), 48 Gy in 6 fractions (n = 4), and 60 Gy in 5 fractions (n = 5). The local tumor control rate at two years was better in patients with early stage lung cancer than patients with lung metastasis: 85% versus 64% (p = 0.21, Fig. 1B). The actuarial overall survival for the whole group was 60% at 2 years and 50% at 3 years. The actuarial overall survival at 2 years was 53% in patients with early stage lung cancer and 75% in patients
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J.J. Nuyttens et al. / Radiotherapy and Oncology 102 (2012) 383–387 Table 2 Dosimetric characteristics of the organs at risk receiving more than 65 Gy3 (EQD2) or 110 BED.
Main bronchi Trachea Esophagus Plexus brachialis
Median Dmax in EQD2 (range)
Median Dmax in BED (range)
Median V65 in cm3 (range)
Number of patients
148 (78–236) 101 (83–131) 88 (68–112) 83 (73–90)
246 168 143 140
2.1 (0.01–13.8) 1.1 (0.01–7.4) 0.3 (0.002–4.7) 0.09 (0.02–0.2)
43 9 18 4
(130–394) (139–219) (112–188) (122–150)
with lung metastasis (p = 0.56, Fig. 2). Twenty-seven patients died: 13 due to tumor progression and 14 due to comorbid disease. The 3year cancer-specific survival was 80% for early stage lung cancer patients, compared to 58% for patients with lung metastases. No acute or late grade 4 or 5 toxicity was recorded. The acute and late complications are shown in Table 3. The cause of the acute grade 3 pneumonitis was probably exacerbation of COPD, but could have been related to the radiotherapy treatment. Two patients (4%) with large PTVs (>150 cm3) were diagnosed with rib fractures. The rib fractures were diagnosed 12 months after the treatment or later, and one of the patients did not report pain from the rib fractures. In 3 patients, the late grade 3 pneumonitis was clearly related to the radiotherapy, in the other patients it also could have been exacerbations of COPD. No correlation between toxicity, tumor location and dose to critical organs could be found.
Discussion The tumor-ablative effects of high-dose SBRT for lung cancer can be safely extended to lesions in the central chest if treatment is adapted to reduce the risk of OAR injury. Several studies have now shown that delivering lower doses over 4–10 fractions can reduce toxicity of SBRT in the central chest [10,13–18], although doses that are often used in treating peripheral lung lesions can result in serious toxicity and death when delivered to central lesions [6,7,9,19], or can result in at least a higher rate of toxicity than for peripheral lesions [8]. The published studies to date have typically consisted of a mixed population of peripheral and central tumors and included relatively small number of patients (8–27 patients) with central tumors. In some studies in which lower fraction doses were delivered, reduced toxicity seemed to come at the expense of poorer local control. For example, Taremi et al. delivered 50 Gy or 60 Gy in 8 fractions to 20 patients with central lesions (out of 108 patients treated overall), and observed no severe toxicity related to tumor
location [17]. However, seven of the 10 local recurrences were central lesions, five of which were treated with 50 Gy. Chang et al. observed low toxicity but a high recurrence rate (43%) in 7 patients treated to 40 Gy in 4 fractions [14]. A similar combination of low dose (BED < 100 Gy) with relatively low toxicity and relatively low local control was obtained by Onimaru et al. [10] and Guckenberger et al. [20]. We treated several of our patients with doses lower than 50 Gy, and found a statistical trend toward poorer tumor control in these patients, a finding that is consistent with these reports. Other authors, however, have reported the ability to deliver doses equal to or above BED = 100 Gy, resulting in the combination of good tumor control (>85% at 1.5–2 years) and low toxicity [15,16,18]. Stephans et al. for example, were able to treat central lung lesions without serious toxicity either using 50 Gy delivered in 5 fractions. Patients were immobilized in a stereotactic frame and abdominal compression was applied to reduce tumor motion. Tumor control at a median follow-up of 18.4 months was 98%. We were also able to deliver doses above BED = 100 Gy, and as previously noted obtained superior disease control relative to lower doses. However, Takeda et al. found a significant lower local control after SBRT with 50 Gy in 5 fractions in patients with oligometastatic tumors from colorectal cancer compared to patients with primary lung cancer (2-year local control rates of 73% compared to 95%) [21]. Thus, we have a highly mixed scenario in the literature: high central doses are often correlated with high toxicity and good tumor control, and low doses are often correlated with low toxicity and poor tumor control. But in some reports high doses were shown to be safely delivered and lower doses have yielded good tumor control. It is not clear how these studies differ, but there are differences in the definition of ‘‘central’’ lesions. Exclusions of lesions too near critical structures such as the hilum and the esophagus may have resulted in differences in patient selection that magnified or allayed toxicity concerns. For example, Stephans et al. delivered a lower dose, 50 Gy in 10 fractions, to 6 patients with large-volume tumors adjacent to critical structures, but these
Fig. 1. (A) Local control according to dose. (B) Local control for early stage lung cancer and lung metastases.
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Stereotactic radiotherapy for tumors central in the lung
Fig. 2. Overall survival for metastatic patients and patients with early stage lung cancer.
patients were excluded from their report; they reported outcomes only for the 7 patients who received 50 Gy in 5 fractions, who presumably did not have lesions adjacent to critical structures. Another reason for this difference in local control and toxicity could be the dose coverage of the PTV and GTV. In 36% of the tumors, we underdosed the PTV to avoid toxicity. This information is not given in the other published articles on central tumor treatment. Underdosage to the PTV and GTV could be a cause of higher local failure, but this was not a statistically significant effect in our population. Some authors have reported low toxicity [15,16,18]. However five other publications report death due to pulmonal complications and two due to esophageal complications. Two authors [8,19] reported the death of one patient secondary to bronchial stenosis and subsequent bleeding from the bronchus. In one patient, the dose to the tumor was 48 Gy in 4 fractions, in the other patient the dose was not specified (but was probably 60 Gy in 4 fractions, based on other details in the report). Milano et al. reported one death due to fatal hemoptysis after treatment of a mediastinal mass abutting the bronchus [22]. The cumulative dose to the bronchus was 98 Gy. Le et al. reported 2 deaths due to pulmonary complications [6]. Both patients were treated previously with radiotherapy to the chest. Fakaris et al. reported five grade 5 toxicities, all possibly related to the stereotactic treatment of 22 patients, and three of them due to pneumonia, one to hemoptysis and one to respiratory failure [9]. Le et al reported the death of one patient due to esophageal fistula followed by a fatal hemoptysis from a tracheovascular fistula. Brachial plexopathy has been reported in 2 patients: one patient developed a brachial plexopathy that was managed medically, however, the dose to the plexus was not reported [13]. The other one developed brachial plexus neuropathy and partial arm paralysis after receiving a dose of 40 Gy (in 4 fractions) to a significant volume of the plexus [14]. Table 3 Acute and late complications (number of patients). Acute complications
Esophagitis Thoracic pain Pneumonitis
Late complications
Grade 1
Grade 2
Grade 3
Grade 1
Grade 2
Grade 3
6 2 11
4 1 6
0 0 4
2 2 4
0 4 7
0 0 6
In the present study of 58 patients, toxicity rates were among the lowest reported to date at all doses delivered, although the medium maximum dose to the main bronchi was 146 Gy3 and 88 Gy3 for the esophagus. This information has not been reported in previous published articles. We believe that risk-adapted treatment of central lesions requires both a consideration of the maximum overall and fraction doses and care to optimize the dose distribution to meet strict dose constraints for sensitive central structures, because several authors did report grades 4 and 5 toxicity. The fact that even doses as low of 40 Gy can cause significant complications points to the critical importance of careful treatment planning, accurate patient setup, and precise radiation delivery throughout a treatment fraction [19]. Toward this goal we have benefited greatly from the ability to use small margins of 5 mm around the GTV. The small margins could be achieved by the use of in-room inter-fraction and intra-fraction tumor motion compensation by the respiratory tracking system. For this system, a targeting error of less than 1.5 mm was achieved routinely [23–25]. Using this method, 2-year tumor control and overall survival have been comparable to that generally reported for SBRT of peripheral NSCLC lesions for patients treated to BED = 100 Gy, and toxicity has been among the lowest reported for central lesions. Conclusion Four-dimensional lung tumor tracking is feasible for central tumors. The local tumor control rate was 76% at two years. Local tumor control was better in patients with early stage lung cancer compared to patients with metastasis. The actuarial overall survival at 2 years was 54% in patients with early stage lung cancer and 75% in patients with lung metastasis. Esophagus toxicity was low when applying a maximum EQD2 constraint of 65 Gy or a maximum BED of 82 Gy. References [1] Chi A, Liao Z, Nguyen NP, Xu J, Stea B, Komaki R. Systemic review of the patterns of failure following stereotactic body radiation therapy in early-stage nonsmall-cell lung cancer: clinical implications. Radiother Oncol 2010;94:1–11. [2] Andratschke N, Zimmermann F, Boehm E, et al. Stereotactic radiotherapy of histologically proven inoperable stage I non-small cell lung cancer: patterns of failure. Radiother Oncol 2011;101:245–9. [3] Nath SK, Sandhu AP, Kim D, et al. Locoregional and distant failure following image-guided stereotactic body radiation for early-stage primary lung cancer. Radiother Oncol 2011;99:12–7. [4] Louie AV, Rodrigues G, Hannouf M, et al. Withholding stereotactic radiotherapy in elderly patients with stage I non-small cell lung cancer and co-existing COPD is not justified: outcomes of a Markov model analysis. Radiother Oncol 2011;99:161–5. [5] van der Voort van Zyp NC, van der Holt B, van Klaveren RJ, Pattynama P, Maat A, Nuyttens JJ. Stereotactic body radiotherapy using real-time tumor tracking in octogenarians with non-small cell lung cancer. Lung Cancer 2010;69:296–301. [6] Le QT, Loo BW, Ho A, et al. Results of a phase I dose-escalation study using single-fraction stereotactic radiotherapy for lung tumors. J Thorac Oncol 2006;1:802–9. [7] Timmerman R, McGarry R, Yiannoutsos C, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol 2006;24:4833–9. [8] Bral S, Gevaert T, Linthout N, et al. Prospective, risk-adapted strategy of stereotactic body radiotherapy for early-stage non-small-cell lung cancer: results of a phase II trial. Int J Radiat Oncol Biol Phys 2011;80:1343–9. [9] Fakiris AJ, McGarry RC, Yiannoutsos CT, et al. Stereotactic body radiation therapy for early-stage non-small-cell lung carcinoma: four-year results of a prospective phase II study. Int J Radiat Oncol Biol Phys 2009;75:677–82. [10] Onimaru R, Shirato H, Shimizu S, et al. Tolerance of organs at risk in smallvolume, hypofractionated, image-guided radiotherapy for primary and metastatic lung cancers. Int J Radiat Oncol Biol Phys 2003;56:126–35. [11] Prevost JB, Voet P, Hoogeman M, Praag J, Levendag P, Nuyttens JJ. Fourdimensional stereotactic radiotherapy for early stage non-small cell lung cancer: a comparative planning study. Technol Cancer Res Treat 2008;7:27–34. [12] van der Voort van Zyp NC, Prevost JB, van der Holt B, et al. Quality of life after stereotactic radiotherapy for stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2010;77:31–7.
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