Technology in Cancer Research and Treatment ISSN 1533-0346 2014 June 30. Epub ahead of print.
Excellent Cancer Outcomes Following Patient-adapted Robotic Lung SBRT But a Case for Caution in Idiopathic Pulmonary Fibrosis www.tcrt.org DOI: 10.7785/tcrt.2012.500445 The aim of this study is to report outcomes and prognostic factors for early stage non-small cell lung cancer treated with patient-adapted Cyberknife stereotactic body radiotherapy. A retrospective analysis of 150 patients with T1-2N0 non-small cell lung cancer treated with stereotactic body radiotherapy was conducted. An algorithm based on tumor and patient’s characteristics was used to orient patients towards soft tissue (Xsight Lung), fiducials or adjacent bone (Xsight Spine) tracking. Median biological effective dose without correction for tissue inhomogeneities was 180 Gy10 for peripheral tumors and 113 Gy10 for central tumors. Median follow-up was 22 months. Actuarial 2 years local control, overall survival and disease-specific survival were respectively 96%, 87% and 95%. Every 1 cm increase in tumor diameter was associated with a relative risk for regional or distant relapse of 2 (95%CI 5 1.2-3.6, p 5 0.009). With doses 132 Gy10 and 132 Gy10, local control was 98% vs. 82% (p 5 0.07), disease-specific survival 97% vs. 78% (p 5 0.02) and overall survival 93% vs. 76% (p 5 0.01), respectively. Better disease-specific survival and a trend for better overall survival was observed for peripheral vs. central tumors (96% vs. 79%, p 5 0.05 and 92% vs. 74%, p 5 0.08, respectively). A higher Charlson comordibity score (4) predicted lower overall survival (79% vs. 98%, p 5 0.01). Toxicities included 3 patients with idiopathic pulmonary fibrosis who developed grade 5 pneumonitis and 2 patients with grade 3 pneumonitis. We therefore report excellent local control and disease-specific survival following patientadapted Cyberknife lung stereotactic body radiotherapy. Although toxicities were in general minimal, patients with pulmonary fibrosis might be at greater risk of severe complications. Small size, peripheral location, dose 132 Gy10 and a low Charlson co-morbidity score seem to be associated with better outcomes.
Houda Bahig, M.D.1 Edith Filion, M.D.1 Toni Vu, M.D.1 David Roberge, M.D.1 Louise Lambert, M.D.1 Myriam Bouchard, M.D.2 Caroline Lavoie, M.D.3 Robert Doucet, M.Sc.1 Dominic Béliveau Nadeau, M.Sc.1 Jean Chalaoui, M.D.1 Marie-Pierre Campeau, M.D.1* Radiation Oncology Department,
1
Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada Radiation Oncology Department,
2
Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada Radiation Oncology Department,
3
Centre Hospitalier Universitaire de Québec, Québec, QC, Canada
Key words: Cyberknife; Lung SBRT; Prognostic factors; Pulmonary fibrosis.
Introduction Non-small cell lung cancer (NSCLC) remains the first cause of mortality related to cancer worldwide (1). Anatomic surgical resection (lobectomy or pneumonectomy) remains the standard treatment for stage 1 NSCLC (T1-T2N0M0) with Abbreviations: BED: Biological Effective Dose; CK: Cyberknife; CT: Computed Tomography; CTCAE: Common Toxicity Criteria for Adverse Events; DLCO: Diffusing Capacity for Carbon Monoxide; DRR: Digitally Reconstructed Radiograph; DSS: Disease-specific Survival; FEV1: Forced Expiratory Volume in 1 sec; FDG-PET Scan: 18-Fluoro-2-deoxy-d-glucose Positron Emission Tomographic Scan; GTV: Gross Tumor Volume; HU: Hounsfield Unit; IPF: Idiopathic Pulmonary Fibrosis; ITV: Internal Target Volume; LC: Local Control; MC: Monte Carlo; NSCLC: Non-small Cell Lung Cancer; OS: Overall Survival; PTV: Planning Target Volume; RECIST: Response Evaluation Criteria in Solid Tumors; SBRT: Stereotactic Body Radiotherapy; VIF: Variance Inflation Factor.
*Corresponding author: Marie-Pierre Campeau, M.D. Phone: (514) 890-8254 Fax: (514) 412-7537 E-mail: [email protected]
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2-year overall survival (OS) approaching 70% (2). However, due to their advanced age at diagnosis and multiple comorbidities, a significant proportion of lung cancer patients are not surgical candidates. After the initial multicentric RTOG 0236 study (3) demonstrated LC as high as 90.6% at 3 years, stereotactic body radiotherapy (SBRT) (also referred to as stereotactic ablative radiotherapy in recent literature) became a standard option for inoperable patients with early stage NSCLC. Several subsequent studies (4-8) have confirmed excellent LC between 85% and 100% for peripheral tumors, with minimal toxicities. More recently, comparison studies have found SBRT outcomes to be similar to surgery (2, 9, 10). Central tumors however remain at higher risk of severe grade 3-5 toxicities (47% vs. 16% for peripheral tumors) and therefore a protracted fractionation regimen is currently recommended for tumors in close proximity to the tracheo-bronchial tree (11). The CyberKnife® (CK) robotic stereotactic radiosurgery system (Accuray Inc., Sunnyvale, CA, US) allows for near-real time target tracking. A patient-adapted treatment approach was adopted by our center using one of 3 m ethods: fiducial markers implantation, direct soft tissue tracking (Xsight Lung®) or use of an internal target volume (ITV) (based on 4D computed tomography scan motion) associated with the tracking of adjacent vertebrae (Xsight Spine®) (12). In this study, we report LC, survival and toxicity results as well as prognostic factors in our cohort of early stage NSCLC treated with CK SBRT. Material and Methods Patients Characteristics A retrospective analysis of all patients with early stage NSCLC treated with CK SBRT between July 2009 and December 2011 at our center was conducted. All patients had stage T1N0M0 or T2N0M0 tumors as per the American Joint Committee on Cancer 7th edition and were either ineligible for surgery or refused surgery. Metastatic and recurrent lesions were excluded. Investigations included: blood test including complete blood count and biochemistries, a thoracic computed tomography (CT) scan, bronchoscopy, 18-fluoro-2-deoxy-d-glucose positron emission tomographic (FDG-PET) scan, pulmonary functions tests and, when available, a histological confirmation of NSCLC. When pathological diagnosis could not be obtained, the decision to treat was taken by our multidisciplinary group after considering tumor progression on serial CT scans and FDG-PET uptake. Central tumors were defined as tumors within 2 cm of the tracheobronchial tree or adjacent to the mediastinum, as defined by RTOG 0618 (11). Approval by our institutional ethics review board was obtained for this study.
Patient-adapted Cyberknife Target Tracking Method Cyberknife version 8.5 and treatment planning system version 3.5 were used in this cohort. Selection of optimal CK tracking technique was made in a multidisciplinary meeting including radiation oncologists, radiologists and medical physicists. Choice of technique was based on patients’ risk factors and tumor characteristics using the algorithm presented in Figure 1. Fiducial Markers Implantation: In-treatment tumor tracking was achieved using 3 to 5 radiopaque (Figure 2A) markers placed in or near the tumor. Transthoracic implantation under CT guidance was favored for most patients but endobronchial or endovascular placements were used in selected cases. Patients with forced expiratory volume in 1 sec (FEV1) of 1 L, large peri-tumoral emphysematous bullae or otherwise technically difficult implantation were excluded from fiducial implantation. Direct Soft Tissue Tracking (Xsight Lung): Tumor tracking was achieved using direct in-treatment soft tissue pattern detection (Figure 2B), obviating the need for fiducial markers implantation. Digitally reconstructed radiographs (DRRs) from the planning CT scan were matched with orthogonal X-rays taken at regular intervals in the treatment room. Patients’ eligibility for this technique was verified with a pretreatment visualisation test. Larger and denser lesions were selected for this treatment method (13). Internal Target Volume (ITV) and Adjacent Vertebrae Tracking (Xsight Spine): In cases of inadequate Xsight Lung tumor detection and unacceptable risks associated with fiducials implantations, an ITV based technique with adjacent vertebrae tracking was considered (Figure 2C).
Figure 1: Patient adapted algorithm for selection of optimal treatment technique. FEV1 5 Forced expiratory volume in 1 second; HT 5 Helical Tomotherapy; RA 5 RapidArc.
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Outcomes and Toxicities of Patient-adapted Lung SBRT
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Figure 2: Digitally reconstructed radiograph (DRR) images labeled synthetic image A and B are extracted from planning computed tomography scan and matched to orthogonal radiograph images (camera image A and B). (A): Three radio-opaque fiducial markers in or near the tumor used for the match. (B) Direct soft tissue pattern recognition is used for tumor match (Xsight lung). (C) Adjacent vertebrae are used for bony anatomy match (Xsight Spine).
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This technique was reserved for tumors in close proximity to adjacent vertebrae with limited motion confirmed by the 4D CT. To limit risks of geographic miss due to shift of the target in relationship to the spine, a 5 mm margin was added to an ITV and larger treatment cones were used. CK Radiotherapy Treatment All patients had a 3 mm slice thickness non-contrast 4D planning CT-scan in supine position. Immobilisation device included a custom foam cushion. Gross tumor volume (GTV) was determined using window level of 600 Hounsfield units (HU) and window width of 1600 HU. An additional planning tumor volume (PTV) margin of 3-5 mm was added to the GTV for fiducials or Xsight Lung cases or to the ITV for Xsight Spine cases. Dose calculation was achieved using Ray-Trace algorithm without corrections for tissue inhomogeneity. Dose was prescribed to a median isodose line of 75% (65-87%), covering at least 95% of the PTV. Lung constraints were as per the STARS Lung Trial and included: the percentage volume of lung (whole lung minus tumor) receiving more than 20 Gy being less than 20% (V20 Gy 20%), V10 Gy 30% and V5 Gy 50%. Dose constraints for all the other organs were as per RTOG 0236 and 0813. Follow-up and Statistical Analysis
literature suggesting decreased outcomes with higher doses (15), treatment regimens were separated a priori into high-dose (60 Gy in 3 fractions–180 Gy10 and 60 Gy in 5 fractions–132 Gy10) and intermediate-to-low dose (50 Gy in 4 fractions–113 Gy10; 50 Gy in 5 fractions–100 Gy10 and 40 Gy in 5 fractions–72 Gy10). Dose (high vs. low-to- intermediate), location (central vs. peripheral), stage, size, histology, CK technique as well as patients age, Charlson co-morbidity score and operability were entered in univariate analysis. Dose, tumor stage and tumor location were selected a priori for multivariate analysis after variance inflation factor (VIF) was used to ensure non-collinearity between variables. Results Patients Characteristics Patients’ characteristics are summarised in Table I. Five patients (3%) had pre-treatment radiological features of idiopathic pulmonary fibrosis (IPF). Histological diagnosis was Table I Patients’ characteristics. Gender (N)
M
42%
F
58%
Age (y)
Tumor response was defined as per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 on followup CT-scans (14). Follow-up CT-scans were obtained every 3 to 6 months in the first year and every 6 months thereafter. A complete response was defined as disappearance of tumor or replacement with radiation fibrosis. Any suspicious residual density after treatment was considered a partial response. Local failure was characterized by a recurrence within 2 cm of the tumor as well as recurrence within the involved lobe. Local relapse was defined as a suspicious mass progression at the site of the primary tumor at least 6 months after SBRT combined with a positive FDG-PET defined by a SUVmax 5 or a biopsy-proven confirmation. Regional failure was defined as recurrence with the hilum or mediastinum. Local recurrence was censored at the time of CT-scan progression. Toxicities were graded as per the Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0.
75 (55-95)
Charlson score
4 (2-14)
Operability (%)
Non operable
82%
Surgery declined
18%
FEV1 (L)
Median
1.4 (0.6-3)
FEV1 (%)
Median
62 (34-137)
DLCO (%)
Median
58 (23-137)
Adenocarcinoma
42%
Squamous cell
25%
Other
17%
Histology (N) Stage (N)
Tumor size (cm) Location (N) CK technique
17% 44%
T1b
39%
T2
18%
Median
2.5 (1.1-4.9)
Peripheral
74%
Central
26%
Fiducials markers
66 (44%)
Follow-up duration was defined as the time from the date of treatment completion to the date of last follow-up or death. Kaplan-Meier method was used for estimation of actuarial local control (LC), overall survival (OS) and disease-specific survival (DSS). Univariate and multivariate cox regression analysis were performed to determine predictors of disease recurrence and survival. With recent
NA T1a
BED (Gy10)
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Xsight Lung
49 (33%)
Xsight Spine
35 (23%)
Median
180 (72-180)
Peripheral
180 (72-180)
Central
113 (106-180); p 5 0.9
T1
180 (72-180)
T2
132 (72-180); p 5 0.9
Outcomes and Toxicities of Patient-adapted Lung SBRT not available for 17% of patients for the following reasons: biopsy was medically contraindicated or technically difficult due to tumor localization (8% patients), unsuccessful attempts (2% had one attempt, 2% had two), suspicious but non diagnostic cytology (3%) and patient refusal (2%). In patients treated with the Xsight Spine technique, the median volume increased with additional margin using an ITV technique was 1.7 cm3 (0-12 cm3). Median delivered dose was 60 Gy (40-60) in 3 fractions (3-5). Total treatment time included an average of 20 minutes for patient set-up, followed by a median treatment time of 21 minutes (range 11-41 minutes). The radiation dose was delivered using a median of 65 nodes (range: 31-153). Local Control and Survival Median follow-up was 22 months. The actuarial 2 years LC, OS and DSS were respectively 96%, 87% and 95% (Figure 3). Local recurrences were biopsy proven for 2 patients (33%) and based on combined suspicious CT progression and SUVmax 5 on FDG-PET for 4 patients
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(67%). Causes of death included progressive lung cancer (6%), radiation pneumonitis (2%), cardiac events (3%), breast cancer (N 5 2) and head and neck cancer (N 5 1). Mortality rate at 90 days was 0.8% for all patients and 0% for operable patients. Local relapse was observed in 6 (5%) patients, regional relapse in 3 (2%) patients and distant relapse in 16 (12%) patients. Based on follow-up CT-scans, best response on last imaging was complete response, partial response and stable disease in 33 (25%), 48 (37%) and 23 (18%) patients, respectively. Prognostic Factors Local control was 98% for patients receiving a biologically effective dose (BED) 132 Gy10 and 82% for patients receiving 113 Gy10 (p 5 0.07). There was no statistically significant difference for LC between peripheral vs. central tumors (96% vs. 89%%, p 5 0.2) and between T1a/b vs. T2 tumors (96% vs. 91%, p 5 0.3) (Table II). In this study, a dose 132 Gy10 predicted a better DSS (97% vs. 78%, p 5 0.02) and OS (94% vs. 70%, p 5 0.01) (Figure 3). Peripheral tumors had a better DSS compared to central tumors (96% vs. 79%, p 5 0.05) but difference in OS did not reach statistical significance (92% vs. 74% p 5 0.09). A trend towards a better DSS for T1a/b vs. T2 tumors (96% vs. 82%, p 5 0.07) was found but difference in OS between the 2 groups did not reach statistical significance (92% vs. 83% p 5 0.1) (Figure 4). A Charlson co-moridbity score 4 predicted better OS (98% vs. 79%, p 5 0.01) (Table II). Age, Charlson score, tumor histology, CK techniques and operability were Table II Prognostic factors on univariate analysis and multivariate analysis (OS).
Multivariate (OS only)
Univariate LC
p
DSS
p
OS
p
p
0.01
0.06
BED (Gy10) 132
82%
132
98%
Location
Central
89%
Peripheral
96%
Stage
T2a
91%
T1a/b
96%
Charlson score
Figure 3: Kaplan Meier curves of local control (A) and disease-specific survival (B) as a function of time.
4
92%
4
98%
0.07 NS NS NS
78% 97% 79% 96% 82% 96% 90% 98%
0.02 0.05 0.07 0.06
70% 94% 74% 92% 83% 92% 79% 98%
0.08
NS
NS
NS
0.01
NS
No statistically significant difference for age, histology, tracking technique and operability. Abbreviations: HR: Hazard ratio; CI: Confidence interval.
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Bahig et al. not found to be predictive factors of LC or survival on univariate analysis. On logistic regression, tumor dimension was found to be predictive of regional/distant failure with a relative risk for failure of 2 with every 1 cm increase in tumor size (p 5 0.009, 95%CI 5 1.2-3.6). On multivariate analysis, there was a trend for improved OS with BED 132 Gy10 (HR: 0.77 (95%CI 0.21-1.01; p 5 0.06). Neither tumor stage and location nor patients’ operability were found predictive of failure (local, regional or distant) or OS. Assessment of collinearity between dose, stage and location revealed VIF of 1.6, 1.1 and 1.7 respectively. Toxicities Three of the 5 patients (60%) with radiologic features suggestive of IPF developed grade 5 pneumonitis at a median of 3.2 months (2.6-3.2) from treatment completion. Dosimetry based on Ray-Trace algorithm for these 3 patients is shown in Table III. Treatment plans were retrospectively calculated using Monte Carlo (MC) algorithm and compared to RayTrace algorithm. Differences between Ray-Trace and MC lung V5, V20 and mean lung dose were 0%, 11%, 0.1 Gy for the first patient, 0%, 0% and 0.1 Gy for the second patient and 2%, 0% and 1 Gy for the third patient (Table III). Toxicities otherwise included 2 patients with grade 3 pneumonitis (both peripheral tumors), 8 patients (6%) with grade 2 costal tenderness and 5 patients (4%) with rib fractures. Among 66 patients treated using fiducial tracking, 9 patients (14%) had pneumothorax requiring chest tube placement. Of these, 7 (11%) occurred during combined biopsy plus fiducial implantation procedure. Table III Lung dosimetry details for 3 patients with grade 5 pulmonary fibrosis. Patient 1
Patient 2
Patient 3
GTV (cm3)
36
42
6
PTV (cm3)
82
95
21
Dose
50 Gy/4 fx
50 Gy/4 fx
60 Gy/3 fx
Location
Central
Peripheral
Peripheral
FEV1 (L)
1.9
2.2
2
DLCO (%)
33
28
47
V5 Gy (%)
48
33
21
V20 Gy (%)
21
15
6
Mean dose (Gy)
11
8
5
V5 Gy (%)
48
33
19
V20 Gy (%)
21
15
6
Mean dose (Gy)
11
8
4
Ray-Trace
Monte Carlo
Figure 4: Disease-specific survival. (A) solid line 5 dose 132 Gy10, dotted line 5 dose 132 Gy10; (B) solid line 5 peripheral, dotted line 5 central; (C) solid line 5 T1, dotted line 5 T2.
Abbreviation: DLCO 5 Diffusing capacity for carbon monoxide.
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Outcomes and Toxicities of Patient-adapted Lung SBRT Discussion We report an excellent 2-years actuarial LC of 93% consistent with previous studies reporting LC rates between 85% and 98% at 2-3 years (3, 7, 8, 16, 17). Likewise, our 2 years actuarial OS of 87% is higher than reported rates of 52-72% at 2-3 years. Alternative causes of death in this elderly p opulation with multiple co-morbidities are thought to contribute to these lower OS numbers. The high OS of our cohort could be partly explained by the fact that 18% of patients were surgical candidates. Although most lung SBRT patients in the period covered by the study were treated using the CK (approximately 85%), a small proportion of patients with severe chronic obstructive lung disease (FEV1 1 L) who failed the Xsight Lung test and were not eligible to Xsight Spine were oriented towards alternative methods (RapidArc or Tomotherapy). This may also have contributed to the high OS observed in our cohort. There was no clear bias favoring CK in relationship to DSS as tumors size (a potent prognostic factor (13)) was the most important predictor of eligibility for Xsight Lung. Looking at DSS, our rate of 96% at 2 years is comparable to rates following surgery (17, 18). On the other hand, whereas our cohort’s 90-day mortality rate was 0.8%, a recent study reported rates of up to 6% with surgery (both extensive and limited resections) (19). Predictive Factors Better outcomes were associated with BED 132 Gy10 (trend towards better LC, better DSS and OS), smaller tumors (lower regional and distant failure and a trend towards improved DSS) and peripheral tumors (better DSS). There is currently limited data available on optimal lung SBRT dose regimen balancing best outcomes with treatment risks. In a retrospective study, Onishi (22) found better LC and OS at 5 years for patients treated with BED 100 Gy10 vs. BED 100 Gy10 (LC of 92% vs. 57% and OS of 70.8 vs. 30.2%, respectively). In our study, better survival outcomes were found with BED 132 Gy10, corresponding to a regimen of 60 Gy in 3-5 fractions. Lower median dose to central tumors (median BED 113 Gy10, vs. 160 Gy10 for peripheral) and T2 tumors (median of 132 Gy10 vs. 180 Gy10 for T1) could partly explain this finding. After Timmerman (11) reported excessive toxicities for central lesions treated with doses of 60-66 Gy in 3 fractions (47 vs. 16% of grade 3 toxicities), adequate dose to central lesions became controversial. More recently, a systematic review by Senthi (20) reported 8.6% rate of high grade toxicities for central tumors using various dose and fractionation regimen (median BED from 60 to 180 Gy10). Treatment mortality rate was 2.7 % overall and 1% when BED was below 105 Gy10 (normal tissue equivalent dose of 210 Gy3). No difference in OS was found between central and peripheral tumors but LC outcomes were contradictory
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between studies. In general, LC was found to be 85% when BED was 100 Gy10. However, interpretation of this data is difficult considering patients, treatment planning and radiation delivery heterogeneities. In our study, risk-adapted doses to centrally located lesions resulted in minimal toxicities but could in part explain the lower DSS rate in this subgroup. The currently ongoing phase I RTOG 0813 trial aims at determining the maximal tolerated dose to centrally located tumors and has the potential to provide answers about optimal dose regimen for these lesions. Given the anatomical location of central tumors, a theoretical alternate explanation for the lower DSS could be that of a higher propensity of undetected regional micrometastases at the time of diagnosis. Several studies have shown decreased outcomes with larger tumors with LC differences in the order of 20% between T1 and T2 tumors at 2-5 years (21, 22). In a study by Baumann (8), the estimated risk of all failures (local, regional and distant) was significantly increased for stage T2 tumors (41% vs. 18%). A prospective study by Hoyer (23) was the only study showing a difference in DSS between T2 and T1 tumors. In our series, larger tumor dimension was associated with higher rates of regional and distant metastasis and a worse DSS for T2 tumors, which is consistent with the current literature. The impact of larger tumors with regard to treatment dose is currently unclear. In our cohort, although median dose to T2 tumors was reduced, delivered dose was not tailored by tumor size but rather limited by dose constraints to organs at risk. The lower delivered dose could have contributed, at least partly, to the lower outcomes observed for larger tumors. The small number of events (only 6 LR) along with the retrospective nature of the study constitute a limitation to our results. Borderline statistical significance reported for several predictive factors should be considered with caution and be regarded mainly as potential tracks to be further evaluated in future studies. In addition, LR was defined by mass progression on CT and SUVmax 5 on FDG-PET for 4 out of 6 LR. Definition of LR post SBRT remains challenging and emerging data attempts to identify high-risk features in order increase sensitivity and specificity of current imaging (24, 25). Other metrics suggested to be predictive of recurrence such as sequential enlarging opacity, enlarging opacity after 12 months, bulging margins, loss of linear margin or air bronchogram loss were not evaluated in this study. Optimal identification of early LR remains to be defined and these high risks features need to be evaluated in further clinical studies. Toxicities and Pulmonary Fibrosis Although toxicities from lung SBRT are considered minimal, reported rates of radiation pneumonitis requiring clinical intervention range from 0% to 29% (7, 26-28). A large Japanese survey (7) of 2390 patients treated with SBRT reported
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a rate of treatment related deaths of 0.6%. The majority of deaths were related to pulmonary toxicities but association with IPF was not reported. Takeda (29) described the first patient with subclinical IPF who developed an exacerbation of pulmonary symptoms post-SBRT. In a subsequent study by the same author (30), among 133 lung SBRT patients, 2 of 7 patients with grade 3 pulmonary toxicities had IPF. Several subsequent Japanese studies recently reported IPF as a potential predictor of pulmonary toxicities after lung SBRT. Yamashita (31) reported 9 of 117 patients (8%) with grade 4-5 RP after lung SBRT; of these, 7 had radiological features of pulmonary fibrosis. In a recent series by Yamaguchi (32), among 16 patients with subclinical interstitial lung disease (untreated and oxygen-free), 2 patients (13%) developed grade 4-5 RP. Although relationship between IPF and RP (grade 2) was not demonstrated, IPF was significantly associated with extensive RP beyond the irradiated field. The large Japanese multi-institutional experience presented by Onishi at the 2013 American Society of Radiation Oncology meeting reported 41% 3 years OS and 6% rate of grade 5 toxicity among lung SBRT patients with underlying IPF (33). The surgical option is also associated with poor outcomes for this patient population. The American College of Chest Physicians and Society of Thoracic Surgeons consensus recently identified patients with IPF as high-risk patients with increased risk of complications following surgical resection with overall reduced survival and increased risk of mortality and pulmonary complication (34-36). In our study, 3 patients with IPF, 2 of which had limited DLCO (28% and 33%), developed grade 5 pneumonitis (2%). Whereas V20 Gy exceeded the RTOG 0236 acceptable limits for patients 1 and 2, the STARS V10 Gy and V20 Gy dose constraints were only exceeded by 1% for patient 1. For these 2 patients with large PTVs of 82 and 95 cm3, these were unavoidable compromises to ensure adequate tumor coverage. A reduction of the prescription dose (113 Gy10) failed to achieve significant reduction of lung dose. Risks of severe toxicities with a curative approach were discussed with these 2 inoperable patients. They opted for a curative treatment with knowledge of the associated risks. For these patients, an increased lung volume irradiation remains a potential explanation to the fatal pneumonitis. IPF is not an established contra-indication to lung SBRT and there is currently no predictive model to assess the probability of radiation pneumonitis. Until we develop a better understanding of the impact of IPF in lung SBRT, we recommend discussing risks of severe toxicities associated to treatment with these patients and application of more severe lung constraints.
Conclusion Excellent LC and DSS are seen with CK lung SBRT. In general, toxicities are minimal but patients with IPF may be at greater risk of severe pulmonary toxicities. Better predictive models of radiation pneumonitis are needed and stricter dose constraints may be required for these patients. Small size, peripheral location and BED 132 Gy10 were all associated with better outcomes. Potential Conflicts of Interest The CHUM radiation oncology department have received monetary compensation from participation of HB, EF and DR to a Cyberknife Symposium. References 1. Parkin, D. M., Bray, F., Ferlay, J., Pisani, P. Estimating the world cancer burden: Globocan 2000. International Journal of Cancer 94, 153-156 (2001). DOI: 10.1002/ijc.1440 2. Solda, F., Lodge, M., Ashley, S., Whitington, A., Goldstraw, P., Brada, M. Stereotactic radiotherapy (SABR) for the treatment of primary non-small cell lung cancer. Systematic review and comparison with a surgical cohort. Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology 109, 1-7 (2013). DOI: 10.1016/j.radonc.2013.09.006 3. Timmerman, R., Paulus, R., Galvin, J., Michalski, J., Straube, W., Bradley, J., Fakiris, A., Bezjak, A., Videtic, G., Johnstone, D., Fowler, J., Gore, E., Choy, H. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA: the Journal of the American Medical Association 303, 1070-1076 (2010). DOI: 10.1001/jama.2010.261 4. Brown, W. T., Wu, X., Amendola, B., Perman, M., Han, H., Fayad, F., Garcia, S., Lewin, A., Abitbol, A., de la Zerda, A., Schwade, J. G. Treatment of early non-small cell lung cancer, stage IA, by imageguided robotic stereotactic radioablation–CyberKnife. Cancer J 13, 87-94 (2007). DOI: 10.1097/PPO.0b013e31803c5415 5. Brown, W. T., Wu, X., Fayad, F., Fowler, J. F., Amendola, B. E., Garcia, S., Han, H., de la Zerda, A., Bossart, E., Huang, Z., Schwade, J. G. CyberKnife radiosurgery for stage I lung cancer: results at 36 months. Clinical Lung Cancer 8, 488-492 (2007). DOI: 10.3816/ CLC.2007.n.033 6. Lagerwaard, F. J., Haasbeek, C. J., Smit, E. F., Slotman, B. J., Senan, S. Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small-cell lung cancer. International Journal of Radiation Oncology, Biology, Physics 70, 685-692 (2008). DOI: 10.1016/ j.ijrobp.2007.10.053 7. Nagata, Y., Takayama, K., Matsuo, Y., Norihisa, Y., Mizowaki, T., Sakamoto, T., Sakamoto, M., Mitsumori, M., Shibuya, K., Araki, N., Yano, S., Hiraoka, M. Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame. International Journal of Radiation Oncology, Biology, Physics 63, 1427-1431 (2005). DOI: 10.1016/j.ijrobp.2005.05.034 8. Baumann, P., Nyman, J., Hoyer, M., Wennberg, B., Gagliardi, G., Lax, I., Drugge, N., Ekberg, L., Friesland, S., Johansson, K. A., Lund, J. A., Morhed, E., Nilsson, K., Levin, N., Paludan, M., Sederholm, C., Traberg, A., Wittgren, L., Lewensohn, R. Outcome in a prospective phase II trial of medically inoperable stage I non-smallcell lung cancer patients treated with stereotactic body radiotherapy.
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Outcomes and Toxicities of Patient-adapted Lung SBRT Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 27, 3290-3296 (2009). DOI: 10.1200/ JCO.2008.21.5681 9. Verstegen, N. E., Oosterhuis, J. W., Palma, D. A., Rodrigues, G., Lagerwaard, F. J., van der Elst, A., Mollema, R., van Tets, W. F., Warner, A., Joosten, J. J., Amir, M. I., Haasbeek, C. J., Smit, E. F., Slotman, B. J., Senan, S. Stage I-II non-small-cell lung cancer treated using either stereotactic ablative radiotherapy (SABR) or lobectomy by video-assisted thoracoscopic surgery (VATS): outcomes of a propensity score-matched analysis. Annals of Oncology: Official Journal of the European Society for Medical Oncology (ESMO) 24, 1543-1548 (2013). DOI: 10.1093/annonc/mdt026 10. Louie, A. V., Rodrigues, G., Hannouf, M., Zaric, G. S., Palma, D. A., Cao, J. Q., Yaremko, B. P., Malthaner, R., Mocanu, J. D. Stereotactic body radiotherapy versus surgery for medically operable Stage I non-small-cell lung cancer: a Markov model-based decision analysis. International Journal of Radiation Oncology, Biology, Physics 81, 964-973 (2011). DOI: 10.1016/j.ijrobp.2010.06.040 11. Timmerman, R., McGarry, R., Yiannoutsos, C., Papiez, L., Tudor, K., DeLuca, J., Ewing, M., Abdulrahman, R., DesRosiers, C., Williams, M., Fletcher, J. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 24, 4833-4839 (2006). DOI: 10.1200/JCO.2006.07.5937 12. Fu, D. K. R., Wang, B., Wang, H., Mu, Z., Kuduvalli, G., et al. Fiducial-free lung tumor tracking of cyberknife radiosurgery. International Journal of Radiation Oncology, Biology, Physics, S608-609 (2008). DOI: 10.1016/j.ijrobp.2008.06.235 13. Bahig, H., Campeau, M. P., Vu, T., Doucet, R., Beliveau Nadeau, D., Fortin, B., Roberge, D., Lambert, L., Carrier, J. F., Filion, E. Predictive parameters of cyberknife fiducial-less (XSight lung) applicability for treatment of early non-small cell lung cancer: a single-center experience. International Journal of Radiation Oncology, Biology, Physics (2013). DOI: 10.1016/j.ijrobp.2013.06.2048 14. Therasse, P., Arbuck, S. G., Eisenhauer, E. A., Wanders, J., Kaplan, R. S., Rubinstein, L., Verweij, J., Van Glabbeke, M., van Oosterom, A. T., Christian, M. C., Gwyther, S. G. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. Journal of the National Cancer Institute 92, 205-216 (2000). DOI: 10.1093/jnci/92.3.205 15. Zhang, J., Yang, F., Li, B., Li, H., Liu, J., Huang, W., Wang, D., Yi, Y., Wang, J. Which is the optimal biologically effective dose of stereotactic body radiotherapy for Stage I non-small-cell lung cancer? A meta-analysis. International Journal of Radiation Oncology, B iology, Physics 81, e305-316 (2011). DOI: 10.1016/j.ijrobp.2011.04.034 16. Onishi, H., Shirato, H., Nagata, Y., Hiraoka, M., Fujino, M., Gomi, K., Niibe, Y., Karasawa, K., Hayakawa, K., Takai, Y., Kimura, T., Takeda, A., Ouchi, A., Hareyama, M., Kokubo, M., Hara, R., Itami, J., Yamada, K., Araki, T. Hypofractionated stereotactic radiotherapy (HypoFXSRT) for stage I non-small cell lung cancer: updated results of 257 patients in a Japanese multi-institutional study. Journal of Thoracic Oncology: Official Publication of the International Association for the Study of Lung Cancer 2, S94-100 (2007). DOI: 10.1097/ JTO.0b013e318074de34 17. Grills, I. S., Mangona, V. S., Welsh, R., Chmielewski, G., McInerney, E., Martin, S., Wloch, J., Ye, H., Kestin, L. L. Outcomes after stereotactic lung radiotherapy or wedge resection for stage I non-small-cell lung cancer. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology 28, 928-935 (2010). DOI: 10.1200/JCO.2009.25.0928 18. Ginsberg, R. J., Rubinstein, L. V. Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung
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Cancer Study Group. The Annals of thoracic surgery 60, 615-622; discussion 622-613 (1995). DOI: 10.1016/0003-4975(95)00537-U 19. Powell, H. A., Tata, L. J., Baldwin, D. R., Stanley, R. A., Khakwani, A., Hubbard, R. B. Early mortality after surgical resection for lung cancer: an analysis of the english national lung cancer audit. Thorax 68, 826-834 (2013). DOI: 10.1136/thoraxjnl-2012-203123 20. Senthi, S., Haasbeek, C. J., Slotman, B. J., Senan, S. Outcomes of stereotactic ablative radiotherapy for central lung tumours: a systematic review. Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology 106, 276-282 (2013). DOI: 10.1016/j.radonc.2013.01.004 21. Dunlap, E., Larner, M. J., Read, W. P., Benjamin, D. K., Lau, L. C., Shng, K., Jones, D. R. Size matters: A comparison of T1 and T2 peripheral non-small cell lung cancers treated with stereotactic body radiotherapy (SBRT). Journal of Thoracic and Cardiovascular Surgery 140, 583-589 (2010). DOI: 10.1016/j.jtcvs.2010.01.046 22. Onishi, H., Shirato, H., Nagata, Y., Hiraoka, M., Fujino, M., Gomi, K., Karasawa, K., Hayakawa, K., Niibe, Y., Takai, Y., Kimura, T., Takeda, A., Ouchi, A., Hareyama, M., Kokubo, M., Kozuka, T., Arimoto, T., Hara, R., Itami, J., Araki, T. Stereotactic body radiotherapy (SBRT) for operable stage I non-small-cell lung cancer: can SBRT be comparable to surgery? International Journal of Radiation Oncology, Biology, Physics 81, 1352-1358 (2011). DOI: 10.1016/ j.ijrobp.2009.07.1751 23. Hoyer, M. R. H., Hansen, A. T., Ohlhuis, L., Petersen, J., Nellemann, H., Berthelsen, A. K., Grau, C., Engelholm, S. A., von der Maase, H. Prospective study on stereotactic radiotherapy of limited-stage non–smallcell lung cancer. International Journal of Radiation Oncology, Biology, Physics 66, S128-S135 (2006). DOI: 10.1016/j.ijrobp.2006.01.012 24. Huang, K., Dahele, M., Senan, S., Guckenberger, M., Rodrigues, G. B., Ward, A., Boldt, R. G., Palma, D. A. Radiographic changes after lung stereotactic ablative radiotherapy (SABR)–can we distinguish recurrence from fibrosis? A systematic review of the literature. Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology 102, 335-342 (2012). DOI: 10.1016/j.radonc.2011.12.018 25. Huang, K., Senthi, S., Palma, D. A., Spoelstra, F. O., Warner, A., Slotman, B. J., Senan, S. High-risk CT features for detection of local recurrence after stereotactic ablative radiotherapy for lung cancer. Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology 109, 51-57 (2013). DOI: 10.1016/j.radonc.2013.06.047 26. Yamashita, H., Nakagawa, K., Nakamura, N., Koyanagi, H., Tago, M., Igaki, H., Shiraishi, K., Sasano, N., Ohtomo, K. Exceptionally high incidence of symptomatic grade 2-5 radiation pneumonitis after stereotactic radiation therapy for lung tumors. Radiat Oncol 2, 21 (2007). DOI: 10.1186/1748-717X-2-21 27. Guckenberger, M., Heilman, K., Wulf, J., Mueller, G., Beckmann, G., Flentje, M. Pulmonary injury and tumor response after stereotactic body radiotherapy (SBRT): results of a serial follow-up CT study. Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology 85, 435-442 (2007). DOI: 10.1016/j.radonc.2007.10.044 28. Zimmermann, F. B., Geinitz, H., Schill, S., Thamm, R., N ieder, C., Schratzenstaller, U., Molls, M. Stereotactic hypofractionated radiotherapy in stage I (T1-2 N0 M0) non-small-cell lung cancer (NSCLC). Acta Oncol 45, 796-801 (2006). DOI: 10. 1080/02841860600913210 29. Takeda, A., Enomoto, T., Sanuki, N., Nakajima, T., Takeda, T., Sayama, K., Kunieda, E. Acute exacerbation of subclinical idiopathic pulmonary fibrosis triggered by hypofractionated stereotactic body radiotherapy in a patient with primary lung cancer and slightly focal honeycombing. Radiation Medicine 26, 504-507 (2008). DOI: 10.1007/s11604-008-0261-8
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30. Takeda, A., Ohashi, T., Kunieda, E., Enomoto, T., Sanuki, N., Takeda, T., Shigematsu, N. Early graphical appearance of radiation pneumonitis correlates with the severity of radiation pneumonitis after stereotactic body radiotherapy (SBRT) in patients with lung tumors. International Journal of Radiation Oncology, Biology, Physics 77, 685-690 (2010). DOI: 10.1016/j.ijrobp.2009.06.001 31. Yamashita, H., Kobayashi-Shibata, S., Terahara, A., Okuma, K., Haga, A., Wakui, R., Ohtomo, K., Nakagawa, K. Prescreening based on the presence of CT-scan abnormalities and biomarkers (KL-6 and SP-D) may reduce severe radiation pneumonitis after stereotactic radiotherapy. Radiat Oncol 5, 32 (2010). DOI: 10.1186/1748-717X-5-32 32. Yamaguchi, S., Ohguri, T., Ide, S., Aoki, T., Imada, H., Yahara, K., Narisada, H., Korogi, Y. Stereotactic body radiotherapy for lung tumors in patients with subclinical interstitial lung disease: the potential risk of extensive radiation pneumonitis. Lung Cancer 82, 260-265 (2013). DOI: 10.1016/j.lungcan.2013.08.024 33. Onishi, H. Y. S., Yasuo, M., Kenji, T., Yukinori, M., Akifumi, M., Hideomi, Y., Haruo, M., Masahiko, A., Keiji, N. Japanese multi-institutional study of stereotactic body radiation therapy for more than 2000 patients with stage I non small cell lung cancer.
International Journal of Radiation Oncology * Biology * Physics 87, S9-S10 (2013). DOI: 10.1016/j.ijrobp.2013.06.031 34. Watanabe, A., Higami, T., Ohori, S., Koyanagi, T., Nakashima, S., Mawatari, T. Is lung cancer resection indicated in patients with idiopathic pulmonary fibrosis? The Journal of Thoracic and Cardiovascular Surgery 136, 1357-1363, 1363 e1351-1352 (2008). DOI: 10.1016/j.jtcvs.2008.07.016 35. Donington, J., Ferguson, M., Mazzone, P., Handy, J. Jr., Schuchert, M., Fernando, H., Loo, B. Jr., Lanuti, M., de Hoyos, A., Detterbeck, F., Pennathur, A., Howington, J., Landreneau, R., Silvestri, G. American college of chest physicians and society of thoracic surgeons consensus statement for evaluation and management for high-risk patients with stage I non-small cell lung cancer. Chest 142, 16201635 (2012). DOI: 10.1378/chest.12-0790 36. Chida, M., Ono, S., Hoshikawa, Y., Kondo, T. Subclinical idiopathic pulmonary fibrosis is also a risk factor of postoperative acute respiratory distress syndrome following thoracic surgery. European Journal of Cardio-Thoracic Surgery: Official Journal of the European Association for Cardio-thoracic Surgery 34, 878-881 (2008). DOI: 10.1016/j.ejcts.2008.07.028 Received: January 17, 2014; Revised: March 10, 2014; Accepted: April 4, 2014
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Excellent Cancer Outcomes Following Patient-adapted Robotic Lung SBRT But a Case for Caution in Idiopathic Pulmonary Fibrosis www.tcrt.org DOI: 10.7785/tcrt.2012.500445 The aim of this study is to report outcomes and prognostic factors for early stage non-small cell lung cancer treated with patient-adapted Cyberknife stereotactic body radiotherapy. A retrospective analysis of 150 patients with T1-2N0 non-small cell lung cancer treated with stereotactic body radiotherapy was conducted. An algorithm based on tumor and patient’s characteristics was used to orient patients towards soft tissue (Xsight Lung), fiducials or adjacent bone (Xsight Spine) tracking. Median biological effective dose without correction for tissue inhomogeneities was 180 Gy10 for peripheral tumors and 113 Gy10 for central tumors. Median follow-up was 22 months. Actuarial 2 years local control, overall survival and disease-specific survival were respectively 96%, 87% and 95%. Every 1 cm increase in tumor diameter was associated with a relative risk for regional or distant relapse of 2 (95%CI 5 1.2-3.6, p 5 0.009). With doses 132 Gy10 and 132 Gy10, local control was 98% vs. 82% (p 5 0.07), disease-specific survival 97% vs. 78% (p 5 0.02) and overall survival 93% vs. 76% (p 5 0.01), respectively. Better disease-specific survival and a trend for better overall survival was observed for peripheral vs. central tumors (96% vs. 79%, p 5 0.05 and 92% vs. 74%, p 5 0.08, respectively). A higher Charlson comordibity score (4) predicted lower overall survival (79% vs. 98%, p 5 0.01). Toxicities included 3 patients with idiopathic pulmonary fibrosis who developed grade 5 pneumonitis and 2 patients with grade 3 pneumonitis. We therefore report excellent local control and disease-specific survival following patientadapted Cyberknife lung stereotactic body radiotherapy. Although toxicities were in general minimal, patients with pulmonary fibrosis might be at greater risk of severe complications. Small size, peripheral location, dose 132 Gy10 and a low Charlson co-morbidity score seem to be associated with better outcomes.
Houda Bahig, M.D.1 Edith Filion, M.D.1 Toni Vu, M.D.1 David Roberge, M.D.1 Louise Lambert, M.D.1 Myriam Bouchard, M.D.2 Caroline Lavoie, M.D.3 Robert Doucet, M.Sc.1 Dominic Béliveau Nadeau, M.Sc.1 Jean Chalaoui, M.D.1 Marie-Pierre Campeau, M.D.1* Radiation Oncology Department,
1
Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada Radiation Oncology Department,
2
Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada Radiation Oncology Department,
3
Centre Hospitalier Universitaire de Québec, Québec, QC, Canada
Key words: Cyberknife; Lung SBRT; Prognostic factors; Pulmonary fibrosis.
Introduction Non-small cell lung cancer (NSCLC) remains the first cause of mortality related to cancer worldwide (1). Anatomic surgical resection (lobectomy or pneumonectomy) remains the standard treatment for stage 1 NSCLC (T1-T2N0M0) with Abbreviations: BED: Biological Effective Dose; CK: Cyberknife; CT: Computed Tomography; CTCAE: Common Toxicity Criteria for Adverse Events; DLCO: Diffusing Capacity for Carbon Monoxide; DRR: Digitally Reconstructed Radiograph; DSS: Disease-specific Survival; FEV1: Forced Expiratory Volume in 1 sec; FDG-PET Scan: 18-Fluoro-2-deoxy-d-glucose Positron Emission Tomographic Scan; GTV: Gross Tumor Volume; HU: Hounsfield Unit; IPF: Idiopathic Pulmonary Fibrosis; ITV: Internal Target Volume; LC: Local Control; MC: Monte Carlo; NSCLC: Non-small Cell Lung Cancer; OS: Overall Survival; PTV: Planning Target Volume; RECIST: Response Evaluation Criteria in Solid Tumors; SBRT: Stereotactic Body Radiotherapy; VIF: Variance Inflation Factor.
*Corresponding author: Marie-Pierre Campeau, M.D. Phone: (514) 890-8254 Fax: (514) 412-7537 E-mail: [email protected]
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2-year overall survival (OS) approaching 70% (2). However, due to their advanced age at diagnosis and multiple comorbidities, a significant proportion of lung cancer patients are not surgical candidates. After the initial multicentric RTOG 0236 study (3) demonstrated LC as high as 90.6% at 3 years, stereotactic body radiotherapy (SBRT) (also referred to as stereotactic ablative radiotherapy in recent literature) became a standard option for inoperable patients with early stage NSCLC. Several subsequent studies (4-8) have confirmed excellent LC between 85% and 100% for peripheral tumors, with minimal toxicities. More recently, comparison studies have found SBRT outcomes to be similar to surgery (2, 9, 10). Central tumors however remain at higher risk of severe grade 3-5 toxicities (47% vs. 16% for peripheral tumors) and therefore a protracted fractionation regimen is currently recommended for tumors in close proximity to the tracheo-bronchial tree (11). The CyberKnife® (CK) robotic stereotactic radiosurgery system (Accuray Inc., Sunnyvale, CA, US) allows for near-real time target tracking. A patient-adapted treatment approach was adopted by our center using one of 3 m ethods: fiducial markers implantation, direct soft tissue tracking (Xsight Lung®) or use of an internal target volume (ITV) (based on 4D computed tomography scan motion) associated with the tracking of adjacent vertebrae (Xsight Spine®) (12). In this study, we report LC, survival and toxicity results as well as prognostic factors in our cohort of early stage NSCLC treated with CK SBRT. Material and Methods Patients Characteristics A retrospective analysis of all patients with early stage NSCLC treated with CK SBRT between July 2009 and December 2011 at our center was conducted. All patients had stage T1N0M0 or T2N0M0 tumors as per the American Joint Committee on Cancer 7th edition and were either ineligible for surgery or refused surgery. Metastatic and recurrent lesions were excluded. Investigations included: blood test including complete blood count and biochemistries, a thoracic computed tomography (CT) scan, bronchoscopy, 18-fluoro-2-deoxy-d-glucose positron emission tomographic (FDG-PET) scan, pulmonary functions tests and, when available, a histological confirmation of NSCLC. When pathological diagnosis could not be obtained, the decision to treat was taken by our multidisciplinary group after considering tumor progression on serial CT scans and FDG-PET uptake. Central tumors were defined as tumors within 2 cm of the tracheobronchial tree or adjacent to the mediastinum, as defined by RTOG 0618 (11). Approval by our institutional ethics review board was obtained for this study.
Patient-adapted Cyberknife Target Tracking Method Cyberknife version 8.5 and treatment planning system version 3.5 were used in this cohort. Selection of optimal CK tracking technique was made in a multidisciplinary meeting including radiation oncologists, radiologists and medical physicists. Choice of technique was based on patients’ risk factors and tumor characteristics using the algorithm presented in Figure 1. Fiducial Markers Implantation: In-treatment tumor tracking was achieved using 3 to 5 radiopaque (Figure 2A) markers placed in or near the tumor. Transthoracic implantation under CT guidance was favored for most patients but endobronchial or endovascular placements were used in selected cases. Patients with forced expiratory volume in 1 sec (FEV1) of 1 L, large peri-tumoral emphysematous bullae or otherwise technically difficult implantation were excluded from fiducial implantation. Direct Soft Tissue Tracking (Xsight Lung): Tumor tracking was achieved using direct in-treatment soft tissue pattern detection (Figure 2B), obviating the need for fiducial markers implantation. Digitally reconstructed radiographs (DRRs) from the planning CT scan were matched with orthogonal X-rays taken at regular intervals in the treatment room. Patients’ eligibility for this technique was verified with a pretreatment visualisation test. Larger and denser lesions were selected for this treatment method (13). Internal Target Volume (ITV) and Adjacent Vertebrae Tracking (Xsight Spine): In cases of inadequate Xsight Lung tumor detection and unacceptable risks associated with fiducials implantations, an ITV based technique with adjacent vertebrae tracking was considered (Figure 2C).
Figure 1: Patient adapted algorithm for selection of optimal treatment technique. FEV1 5 Forced expiratory volume in 1 second; HT 5 Helical Tomotherapy; RA 5 RapidArc.
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Outcomes and Toxicities of Patient-adapted Lung SBRT
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Figure 2: Digitally reconstructed radiograph (DRR) images labeled synthetic image A and B are extracted from planning computed tomography scan and matched to orthogonal radiograph images (camera image A and B). (A): Three radio-opaque fiducial markers in or near the tumor used for the match. (B) Direct soft tissue pattern recognition is used for tumor match (Xsight lung). (C) Adjacent vertebrae are used for bony anatomy match (Xsight Spine).
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This technique was reserved for tumors in close proximity to adjacent vertebrae with limited motion confirmed by the 4D CT. To limit risks of geographic miss due to shift of the target in relationship to the spine, a 5 mm margin was added to an ITV and larger treatment cones were used. CK Radiotherapy Treatment All patients had a 3 mm slice thickness non-contrast 4D planning CT-scan in supine position. Immobilisation device included a custom foam cushion. Gross tumor volume (GTV) was determined using window level of 600 Hounsfield units (HU) and window width of 1600 HU. An additional planning tumor volume (PTV) margin of 3-5 mm was added to the GTV for fiducials or Xsight Lung cases or to the ITV for Xsight Spine cases. Dose calculation was achieved using Ray-Trace algorithm without corrections for tissue inhomogeneity. Dose was prescribed to a median isodose line of 75% (65-87%), covering at least 95% of the PTV. Lung constraints were as per the STARS Lung Trial and included: the percentage volume of lung (whole lung minus tumor) receiving more than 20 Gy being less than 20% (V20 Gy 20%), V10 Gy 30% and V5 Gy 50%. Dose constraints for all the other organs were as per RTOG 0236 and 0813. Follow-up and Statistical Analysis
literature suggesting decreased outcomes with higher doses (15), treatment regimens were separated a priori into high-dose (60 Gy in 3 fractions–180 Gy10 and 60 Gy in 5 fractions–132 Gy10) and intermediate-to-low dose (50 Gy in 4 fractions–113 Gy10; 50 Gy in 5 fractions–100 Gy10 and 40 Gy in 5 fractions–72 Gy10). Dose (high vs. low-to- intermediate), location (central vs. peripheral), stage, size, histology, CK technique as well as patients age, Charlson co-morbidity score and operability were entered in univariate analysis. Dose, tumor stage and tumor location were selected a priori for multivariate analysis after variance inflation factor (VIF) was used to ensure non-collinearity between variables. Results Patients Characteristics Patients’ characteristics are summarised in Table I. Five patients (3%) had pre-treatment radiological features of idiopathic pulmonary fibrosis (IPF). Histological diagnosis was Table I Patients’ characteristics. Gender (N)
M
42%
F
58%
Age (y)
Tumor response was defined as per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 on followup CT-scans (14). Follow-up CT-scans were obtained every 3 to 6 months in the first year and every 6 months thereafter. A complete response was defined as disappearance of tumor or replacement with radiation fibrosis. Any suspicious residual density after treatment was considered a partial response. Local failure was characterized by a recurrence within 2 cm of the tumor as well as recurrence within the involved lobe. Local relapse was defined as a suspicious mass progression at the site of the primary tumor at least 6 months after SBRT combined with a positive FDG-PET defined by a SUVmax 5 or a biopsy-proven confirmation. Regional failure was defined as recurrence with the hilum or mediastinum. Local recurrence was censored at the time of CT-scan progression. Toxicities were graded as per the Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0.
75 (55-95)
Charlson score
4 (2-14)
Operability (%)
Non operable
82%
Surgery declined
18%
FEV1 (L)
Median
1.4 (0.6-3)
FEV1 (%)
Median
62 (34-137)
DLCO (%)
Median
58 (23-137)
Adenocarcinoma
42%
Squamous cell
25%
Other
17%
Histology (N) Stage (N)
Tumor size (cm) Location (N) CK technique
17% 44%
T1b
39%
T2
18%
Median
2.5 (1.1-4.9)
Peripheral
74%
Central
26%
Fiducials markers
66 (44%)
Follow-up duration was defined as the time from the date of treatment completion to the date of last follow-up or death. Kaplan-Meier method was used for estimation of actuarial local control (LC), overall survival (OS) and disease-specific survival (DSS). Univariate and multivariate cox regression analysis were performed to determine predictors of disease recurrence and survival. With recent
NA T1a
BED (Gy10)
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Xsight Lung
49 (33%)
Xsight Spine
35 (23%)
Median
180 (72-180)
Peripheral
180 (72-180)
Central
113 (106-180); p 5 0.9
T1
180 (72-180)
T2
132 (72-180); p 5 0.9
Outcomes and Toxicities of Patient-adapted Lung SBRT not available for 17% of patients for the following reasons: biopsy was medically contraindicated or technically difficult due to tumor localization (8% patients), unsuccessful attempts (2% had one attempt, 2% had two), suspicious but non diagnostic cytology (3%) and patient refusal (2%). In patients treated with the Xsight Spine technique, the median volume increased with additional margin using an ITV technique was 1.7 cm3 (0-12 cm3). Median delivered dose was 60 Gy (40-60) in 3 fractions (3-5). Total treatment time included an average of 20 minutes for patient set-up, followed by a median treatment time of 21 minutes (range 11-41 minutes). The radiation dose was delivered using a median of 65 nodes (range: 31-153). Local Control and Survival Median follow-up was 22 months. The actuarial 2 years LC, OS and DSS were respectively 96%, 87% and 95% (Figure 3). Local recurrences were biopsy proven for 2 patients (33%) and based on combined suspicious CT progression and SUVmax 5 on FDG-PET for 4 patients
5
(67%). Causes of death included progressive lung cancer (6%), radiation pneumonitis (2%), cardiac events (3%), breast cancer (N 5 2) and head and neck cancer (N 5 1). Mortality rate at 90 days was 0.8% for all patients and 0% for operable patients. Local relapse was observed in 6 (5%) patients, regional relapse in 3 (2%) patients and distant relapse in 16 (12%) patients. Based on follow-up CT-scans, best response on last imaging was complete response, partial response and stable disease in 33 (25%), 48 (37%) and 23 (18%) patients, respectively. Prognostic Factors Local control was 98% for patients receiving a biologically effective dose (BED) 132 Gy10 and 82% for patients receiving 113 Gy10 (p 5 0.07). There was no statistically significant difference for LC between peripheral vs. central tumors (96% vs. 89%%, p 5 0.2) and between T1a/b vs. T2 tumors (96% vs. 91%, p 5 0.3) (Table II). In this study, a dose 132 Gy10 predicted a better DSS (97% vs. 78%, p 5 0.02) and OS (94% vs. 70%, p 5 0.01) (Figure 3). Peripheral tumors had a better DSS compared to central tumors (96% vs. 79%, p 5 0.05) but difference in OS did not reach statistical significance (92% vs. 74% p 5 0.09). A trend towards a better DSS for T1a/b vs. T2 tumors (96% vs. 82%, p 5 0.07) was found but difference in OS between the 2 groups did not reach statistical significance (92% vs. 83% p 5 0.1) (Figure 4). A Charlson co-moridbity score 4 predicted better OS (98% vs. 79%, p 5 0.01) (Table II). Age, Charlson score, tumor histology, CK techniques and operability were Table II Prognostic factors on univariate analysis and multivariate analysis (OS).
Multivariate (OS only)
Univariate LC
p
DSS
p
OS
p
p
0.01
0.06
BED (Gy10) 132
82%
132
98%
Location
Central
89%
Peripheral
96%
Stage
T2a
91%
T1a/b
96%
Charlson score
Figure 3: Kaplan Meier curves of local control (A) and disease-specific survival (B) as a function of time.
4
92%
4
98%
0.07 NS NS NS
78% 97% 79% 96% 82% 96% 90% 98%
0.02 0.05 0.07 0.06
70% 94% 74% 92% 83% 92% 79% 98%
0.08
NS
NS
NS
0.01
NS
No statistically significant difference for age, histology, tracking technique and operability. Abbreviations: HR: Hazard ratio; CI: Confidence interval.
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Bahig et al. not found to be predictive factors of LC or survival on univariate analysis. On logistic regression, tumor dimension was found to be predictive of regional/distant failure with a relative risk for failure of 2 with every 1 cm increase in tumor size (p 5 0.009, 95%CI 5 1.2-3.6). On multivariate analysis, there was a trend for improved OS with BED 132 Gy10 (HR: 0.77 (95%CI 0.21-1.01; p 5 0.06). Neither tumor stage and location nor patients’ operability were found predictive of failure (local, regional or distant) or OS. Assessment of collinearity between dose, stage and location revealed VIF of 1.6, 1.1 and 1.7 respectively. Toxicities Three of the 5 patients (60%) with radiologic features suggestive of IPF developed grade 5 pneumonitis at a median of 3.2 months (2.6-3.2) from treatment completion. Dosimetry based on Ray-Trace algorithm for these 3 patients is shown in Table III. Treatment plans were retrospectively calculated using Monte Carlo (MC) algorithm and compared to RayTrace algorithm. Differences between Ray-Trace and MC lung V5, V20 and mean lung dose were 0%, 11%, 0.1 Gy for the first patient, 0%, 0% and 0.1 Gy for the second patient and 2%, 0% and 1 Gy for the third patient (Table III). Toxicities otherwise included 2 patients with grade 3 pneumonitis (both peripheral tumors), 8 patients (6%) with grade 2 costal tenderness and 5 patients (4%) with rib fractures. Among 66 patients treated using fiducial tracking, 9 patients (14%) had pneumothorax requiring chest tube placement. Of these, 7 (11%) occurred during combined biopsy plus fiducial implantation procedure. Table III Lung dosimetry details for 3 patients with grade 5 pulmonary fibrosis. Patient 1
Patient 2
Patient 3
GTV (cm3)
36
42
6
PTV (cm3)
82
95
21
Dose
50 Gy/4 fx
50 Gy/4 fx
60 Gy/3 fx
Location
Central
Peripheral
Peripheral
FEV1 (L)
1.9
2.2
2
DLCO (%)
33
28
47
V5 Gy (%)
48
33
21
V20 Gy (%)
21
15
6
Mean dose (Gy)
11
8
5
V5 Gy (%)
48
33
19
V20 Gy (%)
21
15
6
Mean dose (Gy)
11
8
4
Ray-Trace
Monte Carlo
Figure 4: Disease-specific survival. (A) solid line 5 dose 132 Gy10, dotted line 5 dose 132 Gy10; (B) solid line 5 peripheral, dotted line 5 central; (C) solid line 5 T1, dotted line 5 T2.
Abbreviation: DLCO 5 Diffusing capacity for carbon monoxide.
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Outcomes and Toxicities of Patient-adapted Lung SBRT Discussion We report an excellent 2-years actuarial LC of 93% consistent with previous studies reporting LC rates between 85% and 98% at 2-3 years (3, 7, 8, 16, 17). Likewise, our 2 years actuarial OS of 87% is higher than reported rates of 52-72% at 2-3 years. Alternative causes of death in this elderly p opulation with multiple co-morbidities are thought to contribute to these lower OS numbers. The high OS of our cohort could be partly explained by the fact that 18% of patients were surgical candidates. Although most lung SBRT patients in the period covered by the study were treated using the CK (approximately 85%), a small proportion of patients with severe chronic obstructive lung disease (FEV1 1 L) who failed the Xsight Lung test and were not eligible to Xsight Spine were oriented towards alternative methods (RapidArc or Tomotherapy). This may also have contributed to the high OS observed in our cohort. There was no clear bias favoring CK in relationship to DSS as tumors size (a potent prognostic factor (13)) was the most important predictor of eligibility for Xsight Lung. Looking at DSS, our rate of 96% at 2 years is comparable to rates following surgery (17, 18). On the other hand, whereas our cohort’s 90-day mortality rate was 0.8%, a recent study reported rates of up to 6% with surgery (both extensive and limited resections) (19). Predictive Factors Better outcomes were associated with BED 132 Gy10 (trend towards better LC, better DSS and OS), smaller tumors (lower regional and distant failure and a trend towards improved DSS) and peripheral tumors (better DSS). There is currently limited data available on optimal lung SBRT dose regimen balancing best outcomes with treatment risks. In a retrospective study, Onishi (22) found better LC and OS at 5 years for patients treated with BED 100 Gy10 vs. BED 100 Gy10 (LC of 92% vs. 57% and OS of 70.8 vs. 30.2%, respectively). In our study, better survival outcomes were found with BED 132 Gy10, corresponding to a regimen of 60 Gy in 3-5 fractions. Lower median dose to central tumors (median BED 113 Gy10, vs. 160 Gy10 for peripheral) and T2 tumors (median of 132 Gy10 vs. 180 Gy10 for T1) could partly explain this finding. After Timmerman (11) reported excessive toxicities for central lesions treated with doses of 60-66 Gy in 3 fractions (47 vs. 16% of grade 3 toxicities), adequate dose to central lesions became controversial. More recently, a systematic review by Senthi (20) reported 8.6% rate of high grade toxicities for central tumors using various dose and fractionation regimen (median BED from 60 to 180 Gy10). Treatment mortality rate was 2.7 % overall and 1% when BED was below 105 Gy10 (normal tissue equivalent dose of 210 Gy3). No difference in OS was found between central and peripheral tumors but LC outcomes were contradictory
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between studies. In general, LC was found to be 85% when BED was 100 Gy10. However, interpretation of this data is difficult considering patients, treatment planning and radiation delivery heterogeneities. In our study, risk-adapted doses to centrally located lesions resulted in minimal toxicities but could in part explain the lower DSS rate in this subgroup. The currently ongoing phase I RTOG 0813 trial aims at determining the maximal tolerated dose to centrally located tumors and has the potential to provide answers about optimal dose regimen for these lesions. Given the anatomical location of central tumors, a theoretical alternate explanation for the lower DSS could be that of a higher propensity of undetected regional micrometastases at the time of diagnosis. Several studies have shown decreased outcomes with larger tumors with LC differences in the order of 20% between T1 and T2 tumors at 2-5 years (21, 22). In a study by Baumann (8), the estimated risk of all failures (local, regional and distant) was significantly increased for stage T2 tumors (41% vs. 18%). A prospective study by Hoyer (23) was the only study showing a difference in DSS between T2 and T1 tumors. In our series, larger tumor dimension was associated with higher rates of regional and distant metastasis and a worse DSS for T2 tumors, which is consistent with the current literature. The impact of larger tumors with regard to treatment dose is currently unclear. In our cohort, although median dose to T2 tumors was reduced, delivered dose was not tailored by tumor size but rather limited by dose constraints to organs at risk. The lower delivered dose could have contributed, at least partly, to the lower outcomes observed for larger tumors. The small number of events (only 6 LR) along with the retrospective nature of the study constitute a limitation to our results. Borderline statistical significance reported for several predictive factors should be considered with caution and be regarded mainly as potential tracks to be further evaluated in future studies. In addition, LR was defined by mass progression on CT and SUVmax 5 on FDG-PET for 4 out of 6 LR. Definition of LR post SBRT remains challenging and emerging data attempts to identify high-risk features in order increase sensitivity and specificity of current imaging (24, 25). Other metrics suggested to be predictive of recurrence such as sequential enlarging opacity, enlarging opacity after 12 months, bulging margins, loss of linear margin or air bronchogram loss were not evaluated in this study. Optimal identification of early LR remains to be defined and these high risks features need to be evaluated in further clinical studies. Toxicities and Pulmonary Fibrosis Although toxicities from lung SBRT are considered minimal, reported rates of radiation pneumonitis requiring clinical intervention range from 0% to 29% (7, 26-28). A large Japanese survey (7) of 2390 patients treated with SBRT reported
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a rate of treatment related deaths of 0.6%. The majority of deaths were related to pulmonary toxicities but association with IPF was not reported. Takeda (29) described the first patient with subclinical IPF who developed an exacerbation of pulmonary symptoms post-SBRT. In a subsequent study by the same author (30), among 133 lung SBRT patients, 2 of 7 patients with grade 3 pulmonary toxicities had IPF. Several subsequent Japanese studies recently reported IPF as a potential predictor of pulmonary toxicities after lung SBRT. Yamashita (31) reported 9 of 117 patients (8%) with grade 4-5 RP after lung SBRT; of these, 7 had radiological features of pulmonary fibrosis. In a recent series by Yamaguchi (32), among 16 patients with subclinical interstitial lung disease (untreated and oxygen-free), 2 patients (13%) developed grade 4-5 RP. Although relationship between IPF and RP (grade 2) was not demonstrated, IPF was significantly associated with extensive RP beyond the irradiated field. The large Japanese multi-institutional experience presented by Onishi at the 2013 American Society of Radiation Oncology meeting reported 41% 3 years OS and 6% rate of grade 5 toxicity among lung SBRT patients with underlying IPF (33). The surgical option is also associated with poor outcomes for this patient population. The American College of Chest Physicians and Society of Thoracic Surgeons consensus recently identified patients with IPF as high-risk patients with increased risk of complications following surgical resection with overall reduced survival and increased risk of mortality and pulmonary complication (34-36). In our study, 3 patients with IPF, 2 of which had limited DLCO (28% and 33%), developed grade 5 pneumonitis (2%). Whereas V20 Gy exceeded the RTOG 0236 acceptable limits for patients 1 and 2, the STARS V10 Gy and V20 Gy dose constraints were only exceeded by 1% for patient 1. For these 2 patients with large PTVs of 82 and 95 cm3, these were unavoidable compromises to ensure adequate tumor coverage. A reduction of the prescription dose (113 Gy10) failed to achieve significant reduction of lung dose. Risks of severe toxicities with a curative approach were discussed with these 2 inoperable patients. They opted for a curative treatment with knowledge of the associated risks. For these patients, an increased lung volume irradiation remains a potential explanation to the fatal pneumonitis. IPF is not an established contra-indication to lung SBRT and there is currently no predictive model to assess the probability of radiation pneumonitis. Until we develop a better understanding of the impact of IPF in lung SBRT, we recommend discussing risks of severe toxicities associated to treatment with these patients and application of more severe lung constraints.
Conclusion Excellent LC and DSS are seen with CK lung SBRT. In general, toxicities are minimal but patients with IPF may be at greater risk of severe pulmonary toxicities. Better predictive models of radiation pneumonitis are needed and stricter dose constraints may be required for these patients. Small size, peripheral location and BED 132 Gy10 were all associated with better outcomes. Potential Conflicts of Interest The CHUM radiation oncology department have received monetary compensation from participation of HB, EF and DR to a Cyberknife Symposium. References 1. Parkin, D. M., Bray, F., Ferlay, J., Pisani, P. Estimating the world cancer burden: Globocan 2000. International Journal of Cancer 94, 153-156 (2001). DOI: 10.1002/ijc.1440 2. Solda, F., Lodge, M., Ashley, S., Whitington, A., Goldstraw, P., Brada, M. Stereotactic radiotherapy (SABR) for the treatment of primary non-small cell lung cancer. Systematic review and comparison with a surgical cohort. Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology 109, 1-7 (2013). DOI: 10.1016/j.radonc.2013.09.006 3. Timmerman, R., Paulus, R., Galvin, J., Michalski, J., Straube, W., Bradley, J., Fakiris, A., Bezjak, A., Videtic, G., Johnstone, D., Fowler, J., Gore, E., Choy, H. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA: the Journal of the American Medical Association 303, 1070-1076 (2010). DOI: 10.1001/jama.2010.261 4. Brown, W. T., Wu, X., Amendola, B., Perman, M., Han, H., Fayad, F., Garcia, S., Lewin, A., Abitbol, A., de la Zerda, A., Schwade, J. G. Treatment of early non-small cell lung cancer, stage IA, by imageguided robotic stereotactic radioablation–CyberKnife. Cancer J 13, 87-94 (2007). DOI: 10.1097/PPO.0b013e31803c5415 5. Brown, W. T., Wu, X., Fayad, F., Fowler, J. F., Amendola, B. E., Garcia, S., Han, H., de la Zerda, A., Bossart, E., Huang, Z., Schwade, J. G. CyberKnife radiosurgery for stage I lung cancer: results at 36 months. Clinical Lung Cancer 8, 488-492 (2007). DOI: 10.3816/ CLC.2007.n.033 6. Lagerwaard, F. J., Haasbeek, C. J., Smit, E. F., Slotman, B. J., Senan, S. Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small-cell lung cancer. International Journal of Radiation Oncology, Biology, Physics 70, 685-692 (2008). DOI: 10.1016/ j.ijrobp.2007.10.053 7. Nagata, Y., Takayama, K., Matsuo, Y., Norihisa, Y., Mizowaki, T., Sakamoto, T., Sakamoto, M., Mitsumori, M., Shibuya, K., Araki, N., Yano, S., Hiraoka, M. Clinical outcomes of a phase I/II study of 48 Gy of stereotactic body radiotherapy in 4 fractions for primary lung cancer using a stereotactic body frame. International Journal of Radiation Oncology, Biology, Physics 63, 1427-1431 (2005). DOI: 10.1016/j.ijrobp.2005.05.034 8. Baumann, P., Nyman, J., Hoyer, M., Wennberg, B., Gagliardi, G., Lax, I., Drugge, N., Ekberg, L., Friesland, S., Johansson, K. A., Lund, J. A., Morhed, E., Nilsson, K., Levin, N., Paludan, M., Sederholm, C., Traberg, A., Wittgren, L., Lewensohn, R. Outcome in a prospective phase II trial of medically inoperable stage I non-smallcell lung cancer patients treated with stereotactic body radiotherapy.
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