- Email: [email protected]
Stereotactic Body Radiotherapy for Early-Stage Multiple Primary Lung Cancers
Accepted Manuscript Stereotactic Body Radiation Therapy (SBRT) for Early-Stage Multiple Primary Lung Cancers John Nikitas, BA, Todd DeWees, PhD, Sana Rehman, MD, Chris Abraham, MD, Jeff Bradley, MD, Cliff Robinson, MD, Michael Roach, MD PII:
S1525-7304(18)30294-8
DOI:
https://doi.org/10.1016/j.cllc.2018.10.010
Reference:
CLLC 874
To appear in:
Clinical Lung Cancer
Received Date: 28 March 2018 Revised Date:
15 October 2018
Accepted Date: 26 October 2018
Please cite this article as: Nikitas J, DeWees T, Rehman S, Abraham C, Bradley J, Robinson C, Roach M, Stereotactic Body Radiation Therapy (SBRT) for Early-Stage Multiple Primary Lung Cancers, Clinical Lung Cancer (2018), doi: https://doi.org/10.1016/j.cllc.2018.10.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Stereotactic Body Radiation Therapy (SBRT) for Early-Stage Multiple Primary Lung Cancers
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John Nikitas1 BA, Todd DeWees2 PhD, Sana Rehman3 MD, Chris Abraham1 MD, Jeff Bradley1
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MD, Cliff Robinson1 MD, Michael Roach1 MD
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1) Department of Radiation Oncology, Washington University School of Medicine, St. Louis,
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MO, USA
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2) Department Biomedical Statistics and Informatics, Mayo Clinic, Scottsdale, Arizona, USA
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3) Department of Radiation Oncology, Riverside Methodist Hospital, Columbus, Ohio, USA
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Corresponding Author
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Michael Roach
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660 S Euclid Ave
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Campus Box 8224
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St. Louis, MO 63110
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314-362-8567 (phone)
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314-362-8521 (fax)
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[email protected]
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Research reported in this publication was supported by the National Center For Advancing
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Translational Sciences of the National Institutes of Health under Award Number TL1TR002344.
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The content is solely the responsibility of the authors and does not necessarily represent the
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official views of the National Institutes of Health.
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Conflicts of Interest
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None of the authors have conflicts of interest relevant to this study.
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MicroAbstract:
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Outcomes of patients with early stage multiple primary lung cancer (MPLC) were reviewed from
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a prospective database at a high volume institution. Compared to patients receiving a single
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course of stereotactic body radiation therapy (SBRT), MPLC patients receiving multiple courses
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of SBRT or receiving surgery followed by SBRT had no significant detriment in survival,
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freedom from disease progression, or toxicity.
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Abstract
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Background: Patients with multiple primary lung cancers (MPLC) increasingly receive multiple
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courses of stereotactic body radiation therapy (SBRT). We aimed to clarify the efficacy and
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safety of such treatments.
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Patients and Methods: We reviewed a prospective lung SBRT database for patients treated for
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stage I non-small cell lung cancer between June 2004 and December 2015.
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Results: 374 patients received a single course of SBRT, 14 received synchronous SBRT, 48
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received metachronous SBRT alone, and 108 received surgery and metachronous SBRT. Median
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follow-up was 37.0 months for survivors. Patients that received a single course had a three-year
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overall survival (OS) of 54.2% (95% confidence interval [CI], 48.8–59.3%), three-year freedom
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from progression (FFP) of 67.3% (95% CI, 60.9–72.9), and grade ≥3 toxicity of 3.5%. Compared
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to single-course patients, patients receiving metachronous SBRT alone and patients receiving
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surgery and metachronous SBRT had improved OS (79.7% [95% CI, 64.4–88.9%], P<0.0001
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and 95.4% [95% CI, 89.2–98.0%], P<0.0001, respectively) and FFP (85.8% [95% CI, 70.7–
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93.5], P=0.03 and 95.4% [95% CI, 89.2–98.0%], P<0.0001, respectively). Patients receiving
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synchronous SBRT had similar OS (46.4% [95% CI, 19.3–69.9%], P=0.75) and similar FFP
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(57.5% [95% CI, 25.3–80.0%], P=0.17) as single-course patients. There were no significant
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differences in rates of grade ≥3 or ≥1 toxicity between single-course patients and the other
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groups.
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Conclusions: Patients that received either synchronous or metachronous SBRT had no
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significant detriment in OS or toxicity when compared to single-course patients. This supports
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the use of SBRT in patients with MPLC.
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Introduction Lung cancer remains the leading cause of cancer mortality, in the United States and abroad,
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with non-small cell lung cancer (NSCLC) comprising 85% of all cases.1 As a result, there have
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been efforts supported by the U.S. Preventive Services Task Force to diagnose lung cancers at
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earlier and more treatable stages using annual, low-dose computed tomography (CT) for at-risk
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populations.2 These screening efforts are part of the reason why up to 30% of lung cancer cases
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in the United States are now being diagnosed at an early stage, defined as either stage I or II.3
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These early tumors can be successfully resected, with local control rates of up to 96% and
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overall survival (OS) rates of approximately 50-60% at 3 years.4 A significant obstacle to
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treating these patients is that many of them have underlying pulmonary or cardiac comorbidities
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that make them poor surgical candidates.5 Fortunately, stereotactic body radiation therapy
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(SBRT) has emerged as an effective treatment modality for medically inoperable, early-stage
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NSCLC patients, achieving local control rates similar to those of surgery.5
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Current literature regarding disease control and treatment toxicity of SBRT has largely been limited to patients with a single early-stage NSCLC. However, medically inoperable patients
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who are diagnosed with multiple, simultaneous tumors may need to receive parallel courses of
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SBRT, (synchronous treatment). Likewise, medically inoperable patients who develop new
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primary tumors following initial treatment may need additional courses of SBRT (metachronous
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treatment). The efficacy and safety of SBRT for patients with synchronous and metachronous
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early-stage NSCLC is not well defined. Therefore, we retrospectively analyzed the clinical
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outcomes of this cohort of patients at our institution with high volumes of prior surgical patients.
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In contrast to other reports on MPLC, we compare these MPLC clinical outcomes to those of
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patients treated with SBRT for a single early-stage NSCLC at our institution.
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Patients and Methods
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Eligibility Criteria
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An IRB-approved, prospective lung SBRT database was retrospectively analyzed for patients that were first treated with SBRT between June 2004 and December 2015 in the Department of
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Radiation Oncology at Washington University in St. Louis. All patients signed an informed
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consent document for inclusion in this database prior to receiving treatment.
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The selection criteria for this study were as follows: 1) Patients must have American Joint
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Committee on Cancer 7th edition stage IA or IB NSCLC that has been confirmed by pathology or
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clinically diagnosed by virtue of positron emission tomography (PET) and CT findings, if biopsy
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was deemed unsafe. 2) Patients must be free of any other malignancies or metastases at the time
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of SBRT administration. 3) Patients must have received definitive intent treatment. 4) Patients
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must have at least three months of follow-up after SBRT that includes at least one imaging study
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(either PET or CT scan) to assess response to therapy. 5) Patients must have not received prior
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conventionally fractionated thoracic radiation.
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Eligible patients were then separated based on whether they received SBRT alone or first surgery and then SBRT. Patients that received SBRT alone were then separated based on
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whether they were treated with a single course, a synchronous course, or a metachronous course
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of SBRT. Metachronous SBRT courses were defined as treatments more than 3 months apart
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(Figure 1).
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Treatment Methods
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SBRT planning was performed as previously described.6 Patients were immobilized either by Elekta Stereotactic Body Frame (SBF) (Elekta, Crawley, England), BodyFix system (Medical
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Intelligence, Munich, Germany), or Alpha Cradle (Smithers Medical Products, North Canton,
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OH). To characterize tumor motion, patients underwent simulation using four-dimensional CT
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(4DCT), performed using a 16-slice CT (Somatom Sensation 16, Philips Medical, Cleveland,
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OH). If 4DCT showed tumor movement greater than 10 mm in any direction, abdominal
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compression was used in addition to the above immobilization techniques. Patients immobilized
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by BodyFix system additionally received two thoracic CT scans and a helical CT scan. Patients
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immobilized with SBF additionally received a helical CT of the thorax.
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SBRT delivery was performed as previously described.6,7 Maximum intensity projections
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(MIP) were used to set the internal target volume (ITV) for the tumor and its path of motion.
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Planning target volume (PTV) was set as 5 mm around the border of the ITV. Radiation therapy
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was generally delivered using a 7–11 non-coplanar beam arrangement.
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Superposition/convolution algorithms were used to correct for heterogeneity. Dose was delivered
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to ≥95% of the PTV and was most commonly set to the 75 to 85% isodose line (range, 60 and
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90% isodose line). Patients either received 5400 cGy in 3 fractions for peripheral lesions or
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5000–5500 cGy in 5 fractions for tumors that were within 2 cm of the proximal bronchial tree or
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were adjacent to the mediastinal or pericardial pleura. The standards set in RTOG 08138 and
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RTOG 02369 were used for normal tissue dose limits.
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Follow-up
Follow up consisted of physical examination and volumetric imaging with CT or PET/CT every 3 to 4 months after completion of therapy for the first two years and then every 6 months
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thereafter. If there was clinical suspicion for local, regional, or metastatic disease, patients
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underwent repeat assessment and evaluation similar to that at initial diagnosis.
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Overall survival (OS) was calculated starting from the diagnosis date of the first NSCLC.
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The diagnosis dates were defined as the earliest conclusive biopsies or PET scans. Freedom from
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progression (FFP) and local control were calculated starting from the date of the first surgery or
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SBRT fraction. Progression was defined as any primary tumor site, regional, or distant
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progression, identified either through CT or PET scan, that occurred after the completion of
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SBRT. If only one new lesion in the lungs was seen on CT imaging at a follow-up, it was defined
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as a new primary. If more than one lesion in the lungs was seen, it was defined as metastatic
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disease. Patients were censored if deceased but not counted as failure. Local failure was defined
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as any in-field progression that occurred after the completion of SBRT, identified by PET scan.
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It was assessed for each individual tumor that was treated with SBRT. Toxicity was assessed
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according to the Common Terminology Criteria for Adverse Events, versions 4.0.10 This
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assessment was generally performed prospectively by the treating physician. In cases where no
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grade was assigned, this was done by retrospectively interpreting the physician notes. Severe
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toxicity was defined as adverse events that were grade ≥3.
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Statistical Analysis
All statistical comparisons were made between the group of patients that received a single
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course of SBRT and each of the other three treatment groups. Differences in baseline patient
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characteristics were assessed by Fisher’s exact test for gender, Eastern Cooperative Oncology
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Group (ECOG) performance status, percentage of patients that have ever smoked, and
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percentage of tumors that were biopsied. The Wilcoxon Rank-Sum Test was used for the other
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patient characteristics. Cumulative rates of OS, FFP, local control, and toxicity were calculated
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using Kaplan-Meier survival analysis. Significance was calculated using a Wilcoxon test. The
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differences in severe toxicity and overall toxicity were assessed by two-tailed Fisher’s exact
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tests. Values of P<0.05 were considered statistically significant. The PHREG procedure was
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used for the multivariate analysis of the differences in OS and FFP intervals seen between the
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groups. All statistical analyses were performed by IBM SPSS Statistics, version 24 (IBM Corp.,
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Armonk, N.Y., USA) and SAS, version 9.4 (SAS Institute Inc., Cary, N.C., USA).
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Results
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Characteristics
Table 1 shows the characteristics of the 544 eligible patients. 374 patients were treated with a
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single course of SBRT, 14 patients were treated with synchronous courses of SBRT, 48 patients
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were treated with metachronous courses of SBRT alone, and 108 patients were treated first with
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surgery for at least one tumor and then with metachronous SBRT for at least another tumor
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(Figure 1). Median follow-up time for the entire cohort was 26.7 months (range, 3–152 months),
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and 37 months for survivors (range 3–153). Women were 54% of the patients. Median age at the
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time of first diagnosis was 73 (interquartile range (IQR), 67–79), and median age-adjusted
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Charlson Comorbidity Score was 5 (IQR 4–7). Compared to patients that received SBRT for a
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single lesion, patients treated with metachronous SBRT alone (P=0.04) or both surgery and
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metachronous SBRT (P=0.02) had significantly better ECOG Performance Scores. Meanwhile,
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there was no statistical difference in performance scores between single treatment or
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synchronous SBRT patients (P=0.15).
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Clinical Outcomes
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Three-year OS, FFP, and local control rates and their 95% confidence intervals (95% CI) are listed in Table 2. Compared to patients that received a single course of SBRT, patients that
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received metachronous courses of SBRT alone (P<0.0001) and patients that received both
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surgery and metachronous SBRT (P<0.0001) had significantly higher OS. There was no
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significant decrease in OS for patients that received synchronous courses of SBRT (P=0.75,
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Figure 2). Patients that received synchronous courses of SBRT had no significant difference in
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FFP compared to patients that received a single course of SBRT (P=0.17). However, there was a
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significant increase in FFP in patients that received both surgery and metachronous SBRT
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(P<0.0001) and in patients that received metachronous courses of SBRT alone (P=0.03, Figure
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3). Compared to patients that received a single course of SBRT, there appeared to be a decrease
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in local control for patients that received synchronous SBRT treatments (P=0.06). However,
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there was an increase in patients that received metachronous SBRT (P=0.10) and a statistically
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significant increase in patients that received both surgery and SBRT (P=0.007, Figure 4).
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When only patients with at least 1 year of follow-up were included in the analysis,
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patients that received a metachronous course of SBRT (P=0.006) or both surgery and
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metachronous SBRT (P<0.001) continued to have significantly higher OS, while synchronous
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patients still did not have significantly decreased OS (P=0.30). For FFP, the only significant
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change was that the higher FFP in the metachronous group was no longer statistically significant
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(P=0.17) when compared to the single treatment group. For local control, the only significant
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change was that the decrease seen in the synchronous group became statistically significant
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(P<0.001) despite the three-year local control rate staying at 75.0%.
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Multivariate analysis was performed to look for the patient characteristics that predicted OS and FFP interval lengths. The statistically significant patient attributes in order of decreasing
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significance were type of tumor (i.e. single, synchronous, metachronous) (P<0.0001), ECOG
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(P<.0001), gender (P=0.008), and central location (P=0.03). For FFP, the only statistically
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significant attribute was type of tumor (P<0.0001).
Toxicity
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The severe (grade≥3) toxicity rate for patients treated with SBRT for single lesions was 3.5%
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and the overall (any grade) toxicity rate was 29.4%. There was no significant difference in severe
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or overall toxicity rates for patients treated with synchronous SBRT, who had rates of 14.3%
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(P=0.10) and 50% (P=0.14), respectively. Likewise, there was no significant difference in severe
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or overall toxicity rates for patients treated with metachronous SBRT alone, who had rates of
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4.2% (P=0.68) and 37.5% (P=0.24), respectively, or for patients treated with surgery and
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metachronous SBRT, who had rates of 5.6% (P=0.40) and 33.3% (P=0.48), respectively. There
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were 2 total cases of grade 5 toxicities, which consisted of 1 case of hemoptysis in a patient
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treated with SBRT for a single lesion and 1 case of pneumonitis in a patient treated with SBRT
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alone for metachronous lesions (Table 3). When Kaplan-Meier analysis was performed for the
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separate incidences of radiation pneumonitis or chest wall toxicity, there were no significant
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differences between the single treatment group and the other three groups (Figure 5A and 5B).
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Discussion
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For patients with a single stage I NSCLC lesion, SBRT and surgery appear to achieve
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similar OS rates.4,11–14 However, for patients that have either synchronous or metachronous
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multiple primary lung cancers (MPLC), the results have been less encouraging for SBRT. Chang
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et al. studied a sample of 39 synchronous MPLC patients and 62 metachronous MPLC patients
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and found that synchronous SBRT achieved a significantly lower four-year OS rate compared to
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metachronous SBRT (39.7% vs 52.7%) and a significantly lower four-year progression free
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survival (PFS) rate (30.4% vs 75.6%).15 Although Chang et al. did not define PFS, it is likely
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similar to our use of FFP. The PFS rate was numerically larger than the OS rate in their
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synchronous cohort, which means that they also censored patients who were deceased in their
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PFS analysis. These authors also called 7 fractions of 10 Gy each SBRT, while we have limited
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SBRT to 5 fractions. Likewise, a study by Creach et al. used a sample of 15 synchronous
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patients and 48 metachronous patients and found that the two-year OS rate was significantly
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lower for the synchronous group than for the metachronous group (27.5% vs 68.1%), as was the
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two-year PFS rate (0% vs 53.3%).7 This current reports defines synchronous as treatment within
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3 months, while the report of Creach et al. defined synchronous for any patient where two
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pulmonary nodules existed simultaneously. These earlier studies by Chang et al. and Creach et
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al. demonstrate that while SBRT is effective for treating metachronous primary lung cancers, it is
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less effective for treating synchronous cancers, posing a therapeutic challenge. In contrast to
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Chang et al. and Creach et al., our results support the idea that SBRT can be effective for treating
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synchronous lung lesions. We found that our small synchronous SBRT had no significant
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difference in three-year OS (46% vs 54%, P=0.75) and only had a modest decrease in three-year
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local control (75% vs 89%, P=0.18) when compared to the single treatment group.
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There have been a few studies that combined synchronous primary lung cancer patients that
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received SBRT with those that received a combination of surgery and SBRT to achieve a higher
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sample size. However, they did not compare these two subgroups to each other to assess their
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relative efficacy. Shintani et al. studied 18 patients and found a three-year OS rate of 69.1% and
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a PFS rate of 43.2%.18 Griffioen et al. sampled 62 patients and found a two-year OS rate of 56%
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and a PFS rate of 87%.19 Griffioen et al. likewise did not explicitly define PFS, but as it is larger
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than their OS rate, it is likely comparable to our definition of FFP. Both sets of authors
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concluded that synchronous treatments of SBRT were effective which supports our conclusion
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that SBRT serves as an effective treatment for synchronous primary lung cancers.
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A few studies have instead chosen to combine synchronous and metachronous SBRT patients into a single group and they have shown more favorable results for treating synchronous
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or metachronous MPLC. Using a sample of 63 MPLC patients, Owen et al. found that SBRT
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achieved a one-year OS rate of 85% and a one-year PFS rate of 91.9%.16 As their PFS is larger
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than OS, it is more comparable to our definition of FFP. Matthiesen et al. had a sample of 10
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patients and found that 6/10 patients were alive and 20/21 tumors were locally controlled at a
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median follow-up time of 15.5 months.17 However, a limitation of these studies is that most of
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their patients received metachronous SBRT. Therefore, these survival statistics likely represent
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the metachronous and not the synchronous group. Taking this into consideration, these two
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studies confirm our findings about metachronous primary lung cancers. Our study showed that
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metachronous SBRT treatment had significantly higher three-year OS (79.7% vs 54.2%,
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P<0.0001) and a similar three-year local control rate (94.5% vs 89.4%, P=0.24) compared to
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single SBRT treatments.
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We believe that our metachronous SBRT treatment group achieved significantly higher OS than our single SBRT treatment group due to the immortal time bias. Patients who have a shorter
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life expectancy with more comorbid diseases are less likely to manifest metachronous disease.
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Therefore, patients who do manifest metachronous disease will tend to have a longer expected
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life-span. Similarly, we found that patients that received both surgery and metachronous SBRT
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also had a higher OS rate. This likely occurred because patients eligible for surgery, as opposed
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to SBRT, tend to be healthier and have fewer comorbidities, which gives them a longer life
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expectancy. The baseline patient characteristics of this study support this hypothesis, with both
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of these groups having significantly better ECOG performance status scores compared to the
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single treatment group (Table 1). Our multivariate analysis supports this, since the type of
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treatment group the patients were part of was the most important predictor of both OS and FFP.
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Being able to receive metachronous SBRT or qualifying for surgery appears to confer certain
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survival and FFP benefits, even more important than age at diagnosis, ECOG performance status,
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or location of the tumor.
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As for the safety of multiple courses of SBRT, we found that for both severe adverse events
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(grade≥3) and all adverse events, there was no significant difference in the toxicity rates between
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the single treatment group and the other three MPLC groups. Repeating the statistical tests with
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Kaplan-Meier survival analysis also failed to show statistically significant differences between
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the single treatment group and any of the other three groups. This suggests that multiple courses
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of radiation therapy are well-tolerated by patients, without worrisome increases in radiation
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pneumonitis, dermatitis, or chest wall toxicity.
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There are some limitations with this study. The first, as was previously mentioned, is the smaller sample size for the synchronous treatment group. Another limitation is that not all
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patients underwent a biopsy. This was generally due to an increased risk for complications due to
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pulmonary comorbidities. A third limitation was that the toxicity data used in this study was
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physician-reported and in some cases assessed retrospectively. A more robust means of toxicity
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assessment would include consistent use of validated instruments as well as patient reported
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outcomes. A final limitation is that the study is retrospective in nature and subject to inherent
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bias. However, despite these limitations, our results confirm previously published reports and
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serve as a basis for future, larger multi-institutional studies.
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In conclusion, SBRT appears effective and safe for patients with for synchronous and
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metachronous MPLC. However, despite these results, further study and validation against other
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institutional experiences merit examination.
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Clinical Practice Points
293 Smaller retrospective series of patients with multiple, early stage lung cancers (MPLC) receiving
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stereotactic body radiation therapy (SBRT) have been published with differing outcomes. This is
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the first study to compare outcomes of these patients with MPLC directly with those receiving
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SBRT for a single, early stage lung cancer. It did so from a prospective database at a high-
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volume institution. This study is also notable as one of the largest series of previous thoracic
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surgery, followed by SBRT for a second cancer published to date. Most importantly, this
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comparative study with single course SBRT showed no statistically significant increases in
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toxicity in patients who receive SBRT after previous lung surgery or who receive multiple
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courses of SBRT, even courses of SBRT within 3 months of each other. This supports as safe
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the repeated use of SBRT in this population. This study suggests improved disease and survival
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outcomes in patients receiving both surgery and SBRT as well as multiple courses of SBRT
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alone for MPLC, though this could be due to selection bias. In contrast to other studies, it
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showed that the use of SBRT for synchronous MPLC had similar disease outcomes as the use of
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SBRT for a single lung cancer. Together, this supports the use of SBRT for any type of MPLC
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as both safe and effective.
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2012;104(1):19-22. doi:10.1016/j.radonc.2011.12.005.
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Bezjak A, Paulus R, Gaspar LE, et al. Efficacy and Toxicity Analysis of NRG Oncology/RTOG 0813 Trial of Stereotactic Body Radiation Therapy (SBRT) for
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Centrally Located Non-Small Cell Lung Cancer (NSCLC). Int J Radiat Oncol.
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2016;96(2):S8. doi:10.1016/j.ijrobp.2016.06.035.
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9.
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Timmerman RD, Paulus R, Galvin J, et al. Toxicity Analysis of RTOG 0236 Using
Stereotactic Body Radiation Therapy to Treat Medically Inoperable Early Stage Lung
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Cancer Patients. Int J Radiat Oncol • Biol • Phys. 2017;69(3):S86.
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Institute.
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Common Terminology Criteria for Adverse Events v4.0 (CTCAE). National Cancer
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Chang JY, Senan S, Paul MA, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: A pooled analysis of two randomised
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trials. Lancet Oncol. 2015;16(6):630-637. doi:10.1016/S1470-2045(15)70168-3.
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Soldà 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
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review and comparison with a surgical cohort. Radiother Oncol. 2013;109(1):1-7.
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doi:10.1016/j.radonc.2013.09.006. 13.
NSCLC in elderly patients: A population-based matched-pair comparison of stereotactic
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radiotherapy versus surgery. Radiother Oncol. 2011;101(2):240-244.
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Palma D, Visser O, Lagerwaard FJ, Belderbos J, Slotman B, Senan S. Treatment of stage i
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Lagerwaard FJ, Verstegen NE, Haasbeek CJA, et al. Outcomes of stereotactic ablative radiotherapy in patients with potentially operable stage i non-small cell lung cancer. Int J
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Chang JY, Liu Y-H, Zhu Z, et al. Stereotactic ablative radiotherapy: a potentially curable approach to early stage multiple primary lung cancer. Cancer. 2013;119(18):3402-3410.
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doi:10.1002/cncr.28217.
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Owen D, Olivier KR, Mayo CS, et al. Outcomes of stereotactic body radiotherapy (SBRT) treatment of multiple synchronous and recurrent lung nodules. Radiat Oncol. 2015;10:43.
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doi:10.1186/s13014-015-0340-9.
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Matthiesen C, Thompson JS, De La Fuente Herman T, Ahmad S, Herman T. Use of stereotactic body radiation therapy for medically inoperable multiple primary lung cancer.
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J Med Imaging Radiat Oncol. 2012;56(5):561-566. doi:10.1111/j.1754-
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9485.2012.02393.x.
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18.
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Shintani T, Masago K, Takayama K, et al. Stereotactic Body Radiotherapy for Synchronous Primary Lung Cancer: Clinical Outcome of 18 Cases. Clin Lung Cancer.
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2015;16(5):e91-e96. doi:10.1016/j.cllc.2014.12.011.
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19.
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Griffioen GHMJ, Lagerwaard FJ, Haasbeek CJA, Smit EF, Slotman BJ, Senan S. Treatment of multiple primary lung cancers using stereotactic radiotherapy, either with or
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without surgery. Radiother Oncol. 2013;107(3):403-408.
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doi:10.1016/j.radonc.2013.04.026.
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Single
Synchronous
Type of Treatment
Metachronous
P-value
Surgery + SBRT
P-value
P-value
374
14
-
48
-
108
-
Age at diagnosis (years), mean Gender Male Female
73.7
73.4
0.85
72.9
0.44
70.6
<0.01
49.0% 51.0%
14.3% 85.7%
0.01
56.3% 43.7%
52.4
58.0
0.53
51.0
93.6% 6.4%
100% 0%
1.00
97.9% 2.1%
24.6% 55.0% 20.4%
7.7% 84.6% 7.7%
0.15
5.4
5.8
27.7
ECOG Performance Status 0 1 2 Age-adjusted Charlson Comorbidity Score, mean
Tumor Location Central Peripheral Biopsy Performed Yes No
0.01
0.94
57.3
0.18
0.34
94.4% 5.6%
1.00
41.3% 47.8% 10.9%
0.04
36.5% 51.4% 12.2%
0.02
0.35
5.3
0.68
5.8
<0.01
22.7
0.37
44.3
<0.0001
38.7
<0.0001
16.8% 83.2%
14.3% 85.7%
1.00
12.5% 87.5%
0.54
19.4% 80.6%
0.57
85.6% 14.4%
100% 0%
0.23
89.6% 10.4%
0.66
62.0% 38.0%
<0.0001
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Follow-up duration (months), mean
34.3% 65.7%
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Have ever smoked? Yes No
0.36
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Sample Size (n), patients
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Table 1: Patient characteristics at diagnosis. Pairwise comparisons were made between the single SBRT treatment group and each of the other three groups using either Fisher’s exact test or a twosided Wilcoxon test. ECOG=Eastern Cooperative Oncology Group. Bold P-values are significant according to the threshold P<0.05.
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95% CI
Synchronous SBRT
95% CI
Metachronous 95% CI Surgery + SBRT 95% CI SBRT
3-Year OS Rate
54.2%
48.8– 59.3%
46.4%
19.3– 69.9%
79.7%*
64.4– 88.9%
95.4%*
89.2– 98.0%
3-Year FFP Rate
67.3%
60.9– 72.9%
57.5%
25.3– 80.0%
85.8%
70.7– 93.5%
95.4%*
89.2– 98.0%
3-Year Local Control Rate
89.4%
85.3– 93.5%
75.0%
53.8– 96.2%
96.0%
90.3– 100%
98.2%*
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Single SBRT
95.8%– 100%
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Table 2: Clinical Outcomes. * means a statistical difference when compared to the single SBRT cohort.
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Pneumonitis
7
Brachial Plexopathy Bronchial obstruction Dermatitis
36
2
12
4
1
1
11 1
1
3 5
4
1
1
1
2
Pleural Effusion
1
SBRT + Surgery n=108 patients 1 2 3 4 5 15
1
1
3 10
1 4
1
1
1
1
1
2
1
2
1
3
1
14 3.5% 124 29.4% -
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3
1
Hemoptysis
Severe (Grade≥3) % of patients Significance P-value Overall % of patients Significance P-value
3
2
Esophagitis
Other
1
Metachronous n=48 patients 1 2 3 4 5
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Chest Wall 39
Synchronous n=14 patients 1 2 3 4 5
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Grade*
Single n=374 patients 1 2 3 4 5
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2 14.3% n.s. 0.10 8 50% n.s. 0.14
2 4.2% n.s. 0.68 24 37.5% n.s. 0.24
6 5.6% n.s. 0.40 38 33.3% n.s. 0.48
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Table 3: SBRT-related toxicity in each group. *Toxicities were graded according to the Common Terminology Criteria for Adverse Events. Analysis was performed using two-sided Fisher’s exact tests between the single treatment group and each of the other three groups (n.s.; not significant).
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Figure 1: Consort diagram.
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****
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****
Patients at risk
14 48 108
6 mo. 371 14 48 108
12 mo. 329 13 48 108
18 mo. 286 11 48 107
24 mo. 249 6 45 107
30 mo. 208 6 41 105
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0 mo. 374
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n.s.
36 mo. 163 6 32 103
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Figure 2: Overall survival for each group. Kaplan-Meier survival analysis was performed followed by Wilcoxon tests comparing each group to the single SBRT treatment group (n.s.; not significant, ****P<0.0001).
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****
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*
Patients at risk 0 mo. 374 14 48 108
6 mo. 334 12 47 108
12 mo. 254 8 45 107
18 mo. 209 5 42 105
24 mo. 173 3 39 104
30 mo. 133 3 30 102
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n.s.
36 mo. 89 3 25 99
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Figure 3: Freedom from progression for each group. Kaplan-Meier survival analysis was performed followed by Wilcoxon tests comparing each group to the single SBRT treatment group (n.s.; not significant, *P<0.05, ****P<0.0001).
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** n.s.
0.8
Single SBRT Synchronous SBRT Metachronous SBRT Surgery + SBRT …
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n.s.
0.4
Tumors at risk Single Syn Meta Surg+SBRT
0.2
6 mo. 341 26 72 125
12 mo. 270 18 64 122
0.0 0
6
12
18
18 mo. 221 10 59 118
24 mo. 183 6 51 115
30 mo. 142 6 41 109
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0 mo. 373 27 84 127
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0.6
24
30
36 mo. 101 6 35 106 36
Time Since Start of Treatment (months)
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Figure 4: Local control for tumors treated with SBRT in each group. Kaplan-Meier survival analysis was performed followed by Wilcoxon tests comparing each group to the single SBRT treatment group (n.s.; not significant, **P<0.01).
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Cumulative Local Control Rate
1.0
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A
n.s. n.s.
1 .0
Single SBRT Synchronous SBRT Metachronous SBRT Surgery + SBRT
0 .8
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…
0 .6
0 .4
Single Syn Meta Surg+SBRT
0 .2
6 mo. 328 12 47 97
0 .0 0
6
12
Patients at risk 12 mo. 18 mo. 261 218 9 5 46 43 81 75
SC
0 mo. 373 13 47 107
24 mo. 179 4 40 63
30 mo. 137 4 31 53
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Cumulative Freedom from Pneumonitis
n.s.
18
24
36 mo. 98 4 26 44
30
36
Time Since Start of Treatment (months)
B
…
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0.6
Single SBRT Synchronous SBRT Metachronous SBRT Surgery + SBRT
n.s. n.s. n.s.
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0.8
0.4
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Cumulative Freedom from Chest Wall Toxicity
1.0
0 mo. 373 13 47 107
Single Syn Meta Surg+SBRT
0.2
Patients at risk 6 mo. 326 12 45 98
12 mo. 232 7 39 77
18 mo. 182 4 35 70
24 mo. 142 3 32 62
30 mo. 103 3 24 52
36 mo. 69 3 20 44
0.0 0
6
12
18
24
30
36
Time Since Start of Treatment (months)
Figure 5: Freedom from pneumonitis (A) and chest wall toxicity (B). Kaplan-Meier survival analysis was performed followed by Wilcoxon tests comparing each group to the single SBRT treatment group (n.s.; not significant).
S1525-7304(18)30294-8
DOI:
https://doi.org/10.1016/j.cllc.2018.10.010
Reference:
CLLC 874
To appear in:
Clinical Lung Cancer
Received Date: 28 March 2018 Revised Date:
15 October 2018
Accepted Date: 26 October 2018
Please cite this article as: Nikitas J, DeWees T, Rehman S, Abraham C, Bradley J, Robinson C, Roach M, Stereotactic Body Radiation Therapy (SBRT) for Early-Stage Multiple Primary Lung Cancers, Clinical Lung Cancer (2018), doi: https://doi.org/10.1016/j.cllc.2018.10.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Stereotactic Body Radiation Therapy (SBRT) for Early-Stage Multiple Primary Lung Cancers
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John Nikitas1 BA, Todd DeWees2 PhD, Sana Rehman3 MD, Chris Abraham1 MD, Jeff Bradley1
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MD, Cliff Robinson1 MD, Michael Roach1 MD
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1) Department of Radiation Oncology, Washington University School of Medicine, St. Louis,
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MO, USA
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2) Department Biomedical Statistics and Informatics, Mayo Clinic, Scottsdale, Arizona, USA
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3) Department of Radiation Oncology, Riverside Methodist Hospital, Columbus, Ohio, USA
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Corresponding Author
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Michael Roach
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660 S Euclid Ave
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Campus Box 8224
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St. Louis, MO 63110
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314-362-8567 (phone)
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314-362-8521 (fax)
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[email protected]
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Research reported in this publication was supported by the National Center For Advancing
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Translational Sciences of the National Institutes of Health under Award Number TL1TR002344.
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The content is solely the responsibility of the authors and does not necessarily represent the
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official views of the National Institutes of Health.
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Conflicts of Interest
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None of the authors have conflicts of interest relevant to this study.
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MicroAbstract:
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Outcomes of patients with early stage multiple primary lung cancer (MPLC) were reviewed from
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a prospective database at a high volume institution. Compared to patients receiving a single
30
course of stereotactic body radiation therapy (SBRT), MPLC patients receiving multiple courses
31
of SBRT or receiving surgery followed by SBRT had no significant detriment in survival,
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freedom from disease progression, or toxicity.
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Abstract
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Background: Patients with multiple primary lung cancers (MPLC) increasingly receive multiple
35
courses of stereotactic body radiation therapy (SBRT). We aimed to clarify the efficacy and
36
safety of such treatments.
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Patients and Methods: We reviewed a prospective lung SBRT database for patients treated for
38
stage I non-small cell lung cancer between June 2004 and December 2015.
39
Results: 374 patients received a single course of SBRT, 14 received synchronous SBRT, 48
40
received metachronous SBRT alone, and 108 received surgery and metachronous SBRT. Median
41
follow-up was 37.0 months for survivors. Patients that received a single course had a three-year
42
overall survival (OS) of 54.2% (95% confidence interval [CI], 48.8–59.3%), three-year freedom
43
from progression (FFP) of 67.3% (95% CI, 60.9–72.9), and grade ≥3 toxicity of 3.5%. Compared
44
to single-course patients, patients receiving metachronous SBRT alone and patients receiving
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surgery and metachronous SBRT had improved OS (79.7% [95% CI, 64.4–88.9%], P<0.0001
46
and 95.4% [95% CI, 89.2–98.0%], P<0.0001, respectively) and FFP (85.8% [95% CI, 70.7–
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93.5], P=0.03 and 95.4% [95% CI, 89.2–98.0%], P<0.0001, respectively). Patients receiving
48
synchronous SBRT had similar OS (46.4% [95% CI, 19.3–69.9%], P=0.75) and similar FFP
49
(57.5% [95% CI, 25.3–80.0%], P=0.17) as single-course patients. There were no significant
50
differences in rates of grade ≥3 or ≥1 toxicity between single-course patients and the other
51
groups.
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Conclusions: Patients that received either synchronous or metachronous SBRT had no
53
significant detriment in OS or toxicity when compared to single-course patients. This supports
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the use of SBRT in patients with MPLC.
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Introduction Lung cancer remains the leading cause of cancer mortality, in the United States and abroad,
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with non-small cell lung cancer (NSCLC) comprising 85% of all cases.1 As a result, there have
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been efforts supported by the U.S. Preventive Services Task Force to diagnose lung cancers at
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earlier and more treatable stages using annual, low-dose computed tomography (CT) for at-risk
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populations.2 These screening efforts are part of the reason why up to 30% of lung cancer cases
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in the United States are now being diagnosed at an early stage, defined as either stage I or II.3
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These early tumors can be successfully resected, with local control rates of up to 96% and
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overall survival (OS) rates of approximately 50-60% at 3 years.4 A significant obstacle to
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treating these patients is that many of them have underlying pulmonary or cardiac comorbidities
65
that make them poor surgical candidates.5 Fortunately, stereotactic body radiation therapy
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(SBRT) has emerged as an effective treatment modality for medically inoperable, early-stage
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NSCLC patients, achieving local control rates similar to those of surgery.5
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Current literature regarding disease control and treatment toxicity of SBRT has largely been limited to patients with a single early-stage NSCLC. However, medically inoperable patients
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who are diagnosed with multiple, simultaneous tumors may need to receive parallel courses of
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SBRT, (synchronous treatment). Likewise, medically inoperable patients who develop new
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primary tumors following initial treatment may need additional courses of SBRT (metachronous
73
treatment). The efficacy and safety of SBRT for patients with synchronous and metachronous
74
early-stage NSCLC is not well defined. Therefore, we retrospectively analyzed the clinical
75
outcomes of this cohort of patients at our institution with high volumes of prior surgical patients.
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In contrast to other reports on MPLC, we compare these MPLC clinical outcomes to those of
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patients treated with SBRT for a single early-stage NSCLC at our institution.
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Patients and Methods
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Eligibility Criteria
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An IRB-approved, prospective lung SBRT database was retrospectively analyzed for patients that were first treated with SBRT between June 2004 and December 2015 in the Department of
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Radiation Oncology at Washington University in St. Louis. All patients signed an informed
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consent document for inclusion in this database prior to receiving treatment.
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The selection criteria for this study were as follows: 1) Patients must have American Joint
87
Committee on Cancer 7th edition stage IA or IB NSCLC that has been confirmed by pathology or
88
clinically diagnosed by virtue of positron emission tomography (PET) and CT findings, if biopsy
89
was deemed unsafe. 2) Patients must be free of any other malignancies or metastases at the time
90
of SBRT administration. 3) Patients must have received definitive intent treatment. 4) Patients
91
must have at least three months of follow-up after SBRT that includes at least one imaging study
92
(either PET or CT scan) to assess response to therapy. 5) Patients must have not received prior
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conventionally fractionated thoracic radiation.
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Eligible patients were then separated based on whether they received SBRT alone or first surgery and then SBRT. Patients that received SBRT alone were then separated based on
96
whether they were treated with a single course, a synchronous course, or a metachronous course
97
of SBRT. Metachronous SBRT courses were defined as treatments more than 3 months apart
98
(Figure 1).
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Treatment Methods
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SBRT planning was performed as previously described.6 Patients were immobilized either by Elekta Stereotactic Body Frame (SBF) (Elekta, Crawley, England), BodyFix system (Medical
103
Intelligence, Munich, Germany), or Alpha Cradle (Smithers Medical Products, North Canton,
104
OH). To characterize tumor motion, patients underwent simulation using four-dimensional CT
105
(4DCT), performed using a 16-slice CT (Somatom Sensation 16, Philips Medical, Cleveland,
106
OH). If 4DCT showed tumor movement greater than 10 mm in any direction, abdominal
107
compression was used in addition to the above immobilization techniques. Patients immobilized
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by BodyFix system additionally received two thoracic CT scans and a helical CT scan. Patients
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immobilized with SBF additionally received a helical CT of the thorax.
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SBRT delivery was performed as previously described.6,7 Maximum intensity projections
111
(MIP) were used to set the internal target volume (ITV) for the tumor and its path of motion.
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Planning target volume (PTV) was set as 5 mm around the border of the ITV. Radiation therapy
113
was generally delivered using a 7–11 non-coplanar beam arrangement.
114
Superposition/convolution algorithms were used to correct for heterogeneity. Dose was delivered
115
to ≥95% of the PTV and was most commonly set to the 75 to 85% isodose line (range, 60 and
116
90% isodose line). Patients either received 5400 cGy in 3 fractions for peripheral lesions or
117
5000–5500 cGy in 5 fractions for tumors that were within 2 cm of the proximal bronchial tree or
118
were adjacent to the mediastinal or pericardial pleura. The standards set in RTOG 08138 and
119
RTOG 02369 were used for normal tissue dose limits.
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Follow-up
Follow up consisted of physical examination and volumetric imaging with CT or PET/CT every 3 to 4 months after completion of therapy for the first two years and then every 6 months
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thereafter. If there was clinical suspicion for local, regional, or metastatic disease, patients
125
underwent repeat assessment and evaluation similar to that at initial diagnosis.
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Overall survival (OS) was calculated starting from the diagnosis date of the first NSCLC.
129
The diagnosis dates were defined as the earliest conclusive biopsies or PET scans. Freedom from
130
progression (FFP) and local control were calculated starting from the date of the first surgery or
131
SBRT fraction. Progression was defined as any primary tumor site, regional, or distant
132
progression, identified either through CT or PET scan, that occurred after the completion of
133
SBRT. If only one new lesion in the lungs was seen on CT imaging at a follow-up, it was defined
134
as a new primary. If more than one lesion in the lungs was seen, it was defined as metastatic
135
disease. Patients were censored if deceased but not counted as failure. Local failure was defined
136
as any in-field progression that occurred after the completion of SBRT, identified by PET scan.
137
It was assessed for each individual tumor that was treated with SBRT. Toxicity was assessed
138
according to the Common Terminology Criteria for Adverse Events, versions 4.0.10 This
139
assessment was generally performed prospectively by the treating physician. In cases where no
140
grade was assigned, this was done by retrospectively interpreting the physician notes. Severe
141
toxicity was defined as adverse events that were grade ≥3.
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Statistical Analysis
All statistical comparisons were made between the group of patients that received a single
145
course of SBRT and each of the other three treatment groups. Differences in baseline patient
146
characteristics were assessed by Fisher’s exact test for gender, Eastern Cooperative Oncology
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Group (ECOG) performance status, percentage of patients that have ever smoked, and
148
percentage of tumors that were biopsied. The Wilcoxon Rank-Sum Test was used for the other
149
patient characteristics. Cumulative rates of OS, FFP, local control, and toxicity were calculated
150
using Kaplan-Meier survival analysis. Significance was calculated using a Wilcoxon test. The
151
differences in severe toxicity and overall toxicity were assessed by two-tailed Fisher’s exact
152
tests. Values of P<0.05 were considered statistically significant. The PHREG procedure was
153
used for the multivariate analysis of the differences in OS and FFP intervals seen between the
154
groups. All statistical analyses were performed by IBM SPSS Statistics, version 24 (IBM Corp.,
155
Armonk, N.Y., USA) and SAS, version 9.4 (SAS Institute Inc., Cary, N.C., USA).
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Results
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Characteristics
Table 1 shows the characteristics of the 544 eligible patients. 374 patients were treated with a
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single course of SBRT, 14 patients were treated with synchronous courses of SBRT, 48 patients
161
were treated with metachronous courses of SBRT alone, and 108 patients were treated first with
162
surgery for at least one tumor and then with metachronous SBRT for at least another tumor
163
(Figure 1). Median follow-up time for the entire cohort was 26.7 months (range, 3–152 months),
164
and 37 months for survivors (range 3–153). Women were 54% of the patients. Median age at the
165
time of first diagnosis was 73 (interquartile range (IQR), 67–79), and median age-adjusted
166
Charlson Comorbidity Score was 5 (IQR 4–7). Compared to patients that received SBRT for a
167
single lesion, patients treated with metachronous SBRT alone (P=0.04) or both surgery and
168
metachronous SBRT (P=0.02) had significantly better ECOG Performance Scores. Meanwhile,
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169
there was no statistical difference in performance scores between single treatment or
170
synchronous SBRT patients (P=0.15).
171
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Clinical Outcomes
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Three-year OS, FFP, and local control rates and their 95% confidence intervals (95% CI) are listed in Table 2. Compared to patients that received a single course of SBRT, patients that
175
received metachronous courses of SBRT alone (P<0.0001) and patients that received both
176
surgery and metachronous SBRT (P<0.0001) had significantly higher OS. There was no
177
significant decrease in OS for patients that received synchronous courses of SBRT (P=0.75,
178
Figure 2). Patients that received synchronous courses of SBRT had no significant difference in
179
FFP compared to patients that received a single course of SBRT (P=0.17). However, there was a
180
significant increase in FFP in patients that received both surgery and metachronous SBRT
181
(P<0.0001) and in patients that received metachronous courses of SBRT alone (P=0.03, Figure
182
3). Compared to patients that received a single course of SBRT, there appeared to be a decrease
183
in local control for patients that received synchronous SBRT treatments (P=0.06). However,
184
there was an increase in patients that received metachronous SBRT (P=0.10) and a statistically
185
significant increase in patients that received both surgery and SBRT (P=0.007, Figure 4).
186
When only patients with at least 1 year of follow-up were included in the analysis,
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patients that received a metachronous course of SBRT (P=0.006) or both surgery and
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metachronous SBRT (P<0.001) continued to have significantly higher OS, while synchronous
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patients still did not have significantly decreased OS (P=0.30). For FFP, the only significant
190
change was that the higher FFP in the metachronous group was no longer statistically significant
191
(P=0.17) when compared to the single treatment group. For local control, the only significant
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192
change was that the decrease seen in the synchronous group became statistically significant
193
(P<0.001) despite the three-year local control rate staying at 75.0%.
194
Multivariate analysis was performed to look for the patient characteristics that predicted OS and FFP interval lengths. The statistically significant patient attributes in order of decreasing
196
significance were type of tumor (i.e. single, synchronous, metachronous) (P<0.0001), ECOG
197
(P<.0001), gender (P=0.008), and central location (P=0.03). For FFP, the only statistically
198
significant attribute was type of tumor (P<0.0001).
Toxicity
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The severe (grade≥3) toxicity rate for patients treated with SBRT for single lesions was 3.5%
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and the overall (any grade) toxicity rate was 29.4%. There was no significant difference in severe
203
or overall toxicity rates for patients treated with synchronous SBRT, who had rates of 14.3%
204
(P=0.10) and 50% (P=0.14), respectively. Likewise, there was no significant difference in severe
205
or overall toxicity rates for patients treated with metachronous SBRT alone, who had rates of
206
4.2% (P=0.68) and 37.5% (P=0.24), respectively, or for patients treated with surgery and
207
metachronous SBRT, who had rates of 5.6% (P=0.40) and 33.3% (P=0.48), respectively. There
208
were 2 total cases of grade 5 toxicities, which consisted of 1 case of hemoptysis in a patient
209
treated with SBRT for a single lesion and 1 case of pneumonitis in a patient treated with SBRT
210
alone for metachronous lesions (Table 3). When Kaplan-Meier analysis was performed for the
211
separate incidences of radiation pneumonitis or chest wall toxicity, there were no significant
212
differences between the single treatment group and the other three groups (Figure 5A and 5B).
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Discussion
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For patients with a single stage I NSCLC lesion, SBRT and surgery appear to achieve
216
similar OS rates.4,11–14 However, for patients that have either synchronous or metachronous
217
multiple primary lung cancers (MPLC), the results have been less encouraging for SBRT. Chang
218
et al. studied a sample of 39 synchronous MPLC patients and 62 metachronous MPLC patients
219
and found that synchronous SBRT achieved a significantly lower four-year OS rate compared to
220
metachronous SBRT (39.7% vs 52.7%) and a significantly lower four-year progression free
221
survival (PFS) rate (30.4% vs 75.6%).15 Although Chang et al. did not define PFS, it is likely
222
similar to our use of FFP. The PFS rate was numerically larger than the OS rate in their
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synchronous cohort, which means that they also censored patients who were deceased in their
224
PFS analysis. These authors also called 7 fractions of 10 Gy each SBRT, while we have limited
225
SBRT to 5 fractions. Likewise, a study by Creach et al. used a sample of 15 synchronous
226
patients and 48 metachronous patients and found that the two-year OS rate was significantly
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lower for the synchronous group than for the metachronous group (27.5% vs 68.1%), as was the
228
two-year PFS rate (0% vs 53.3%).7 This current reports defines synchronous as treatment within
229
3 months, while the report of Creach et al. defined synchronous for any patient where two
230
pulmonary nodules existed simultaneously. These earlier studies by Chang et al. and Creach et
231
al. demonstrate that while SBRT is effective for treating metachronous primary lung cancers, it is
232
less effective for treating synchronous cancers, posing a therapeutic challenge. In contrast to
233
Chang et al. and Creach et al., our results support the idea that SBRT can be effective for treating
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synchronous lung lesions. We found that our small synchronous SBRT had no significant
235
difference in three-year OS (46% vs 54%, P=0.75) and only had a modest decrease in three-year
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local control (75% vs 89%, P=0.18) when compared to the single treatment group.
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There have been a few studies that combined synchronous primary lung cancer patients that
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received SBRT with those that received a combination of surgery and SBRT to achieve a higher
239
sample size. However, they did not compare these two subgroups to each other to assess their
240
relative efficacy. Shintani et al. studied 18 patients and found a three-year OS rate of 69.1% and
241
a PFS rate of 43.2%.18 Griffioen et al. sampled 62 patients and found a two-year OS rate of 56%
242
and a PFS rate of 87%.19 Griffioen et al. likewise did not explicitly define PFS, but as it is larger
243
than their OS rate, it is likely comparable to our definition of FFP. Both sets of authors
244
concluded that synchronous treatments of SBRT were effective which supports our conclusion
245
that SBRT serves as an effective treatment for synchronous primary lung cancers.
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A few studies have instead chosen to combine synchronous and metachronous SBRT patients into a single group and they have shown more favorable results for treating synchronous
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or metachronous MPLC. Using a sample of 63 MPLC patients, Owen et al. found that SBRT
249
achieved a one-year OS rate of 85% and a one-year PFS rate of 91.9%.16 As their PFS is larger
250
than OS, it is more comparable to our definition of FFP. Matthiesen et al. had a sample of 10
251
patients and found that 6/10 patients were alive and 20/21 tumors were locally controlled at a
252
median follow-up time of 15.5 months.17 However, a limitation of these studies is that most of
253
their patients received metachronous SBRT. Therefore, these survival statistics likely represent
254
the metachronous and not the synchronous group. Taking this into consideration, these two
255
studies confirm our findings about metachronous primary lung cancers. Our study showed that
256
metachronous SBRT treatment had significantly higher three-year OS (79.7% vs 54.2%,
257
P<0.0001) and a similar three-year local control rate (94.5% vs 89.4%, P=0.24) compared to
258
single SBRT treatments.
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We believe that our metachronous SBRT treatment group achieved significantly higher OS than our single SBRT treatment group due to the immortal time bias. Patients who have a shorter
261
life expectancy with more comorbid diseases are less likely to manifest metachronous disease.
262
Therefore, patients who do manifest metachronous disease will tend to have a longer expected
263
life-span. Similarly, we found that patients that received both surgery and metachronous SBRT
264
also had a higher OS rate. This likely occurred because patients eligible for surgery, as opposed
265
to SBRT, tend to be healthier and have fewer comorbidities, which gives them a longer life
266
expectancy. The baseline patient characteristics of this study support this hypothesis, with both
267
of these groups having significantly better ECOG performance status scores compared to the
268
single treatment group (Table 1). Our multivariate analysis supports this, since the type of
269
treatment group the patients were part of was the most important predictor of both OS and FFP.
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Being able to receive metachronous SBRT or qualifying for surgery appears to confer certain
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survival and FFP benefits, even more important than age at diagnosis, ECOG performance status,
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or location of the tumor.
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As for the safety of multiple courses of SBRT, we found that for both severe adverse events
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(grade≥3) and all adverse events, there was no significant difference in the toxicity rates between
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the single treatment group and the other three MPLC groups. Repeating the statistical tests with
276
Kaplan-Meier survival analysis also failed to show statistically significant differences between
277
the single treatment group and any of the other three groups. This suggests that multiple courses
278
of radiation therapy are well-tolerated by patients, without worrisome increases in radiation
279
pneumonitis, dermatitis, or chest wall toxicity.
280 281
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There are some limitations with this study. The first, as was previously mentioned, is the smaller sample size for the synchronous treatment group. Another limitation is that not all
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patients underwent a biopsy. This was generally due to an increased risk for complications due to
283
pulmonary comorbidities. A third limitation was that the toxicity data used in this study was
284
physician-reported and in some cases assessed retrospectively. A more robust means of toxicity
285
assessment would include consistent use of validated instruments as well as patient reported
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outcomes. A final limitation is that the study is retrospective in nature and subject to inherent
287
bias. However, despite these limitations, our results confirm previously published reports and
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serve as a basis for future, larger multi-institutional studies.
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In conclusion, SBRT appears effective and safe for patients with for synchronous and
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metachronous MPLC. However, despite these results, further study and validation against other
291
institutional experiences merit examination.
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Clinical Practice Points
293 Smaller retrospective series of patients with multiple, early stage lung cancers (MPLC) receiving
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stereotactic body radiation therapy (SBRT) have been published with differing outcomes. This is
296
the first study to compare outcomes of these patients with MPLC directly with those receiving
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SBRT for a single, early stage lung cancer. It did so from a prospective database at a high-
298
volume institution. This study is also notable as one of the largest series of previous thoracic
299
surgery, followed by SBRT for a second cancer published to date. Most importantly, this
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comparative study with single course SBRT showed no statistically significant increases in
301
toxicity in patients who receive SBRT after previous lung surgery or who receive multiple
302
courses of SBRT, even courses of SBRT within 3 months of each other. This supports as safe
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the repeated use of SBRT in this population. This study suggests improved disease and survival
304
outcomes in patients receiving both surgery and SBRT as well as multiple courses of SBRT
305
alone for MPLC, though this could be due to selection bias. In contrast to other studies, it
306
showed that the use of SBRT for synchronous MPLC had similar disease outcomes as the use of
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SBRT for a single lung cancer. Together, this supports the use of SBRT for any type of MPLC
308
as both safe and effective.
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References
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Bezjak A, Paulus R, Gaspar LE, et al. Efficacy and Toxicity Analysis of NRG Oncology/RTOG 0813 Trial of Stereotactic Body Radiation Therapy (SBRT) for
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Timmerman RD, Paulus R, Galvin J, et al. Toxicity Analysis of RTOG 0236 Using
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Chang JY, Senan S, Paul MA, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: A pooled analysis of two randomised
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Soldà 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
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NSCLC in elderly patients: A population-based matched-pair comparison of stereotactic
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Lagerwaard FJ, Verstegen NE, Haasbeek CJA, et al. Outcomes of stereotactic ablative radiotherapy in patients with potentially operable stage i non-small cell lung cancer. Int J
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Chang JY, Liu Y-H, Zhu Z, et al. Stereotactic ablative radiotherapy: a potentially curable approach to early stage multiple primary lung cancer. Cancer. 2013;119(18):3402-3410.
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Owen D, Olivier KR, Mayo CS, et al. Outcomes of stereotactic body radiotherapy (SBRT) treatment of multiple synchronous and recurrent lung nodules. Radiat Oncol. 2015;10:43.
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Matthiesen C, Thompson JS, De La Fuente Herman T, Ahmad S, Herman T. Use of stereotactic body radiation therapy for medically inoperable multiple primary lung cancer.
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Shintani T, Masago K, Takayama K, et al. Stereotactic Body Radiotherapy for Synchronous Primary Lung Cancer: Clinical Outcome of 18 Cases. Clin Lung Cancer.
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Griffioen GHMJ, Lagerwaard FJ, Haasbeek CJA, Smit EF, Slotman BJ, Senan S. Treatment of multiple primary lung cancers using stereotactic radiotherapy, either with or
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Single
Synchronous
Type of Treatment
Metachronous
P-value
Surgery + SBRT
P-value
P-value
374
14
-
48
-
108
-
Age at diagnosis (years), mean Gender Male Female
73.7
73.4
0.85
72.9
0.44
70.6
<0.01
49.0% 51.0%
14.3% 85.7%
0.01
56.3% 43.7%
52.4
58.0
0.53
51.0
93.6% 6.4%
100% 0%
1.00
97.9% 2.1%
24.6% 55.0% 20.4%
7.7% 84.6% 7.7%
0.15
5.4
5.8
27.7
ECOG Performance Status 0 1 2 Age-adjusted Charlson Comorbidity Score, mean
Tumor Location Central Peripheral Biopsy Performed Yes No
0.01
0.94
57.3
0.18
0.34
94.4% 5.6%
1.00
41.3% 47.8% 10.9%
0.04
36.5% 51.4% 12.2%
0.02
0.35
5.3
0.68
5.8
<0.01
22.7
0.37
44.3
<0.0001
38.7
<0.0001
16.8% 83.2%
14.3% 85.7%
1.00
12.5% 87.5%
0.54
19.4% 80.6%
0.57
85.6% 14.4%
100% 0%
0.23
89.6% 10.4%
0.66
62.0% 38.0%
<0.0001
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Follow-up duration (months), mean
34.3% 65.7%
SC
Have ever smoked? Yes No
0.36
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Sample Size (n), patients
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Table 1: Patient characteristics at diagnosis. Pairwise comparisons were made between the single SBRT treatment group and each of the other three groups using either Fisher’s exact test or a twosided Wilcoxon test. ECOG=Eastern Cooperative Oncology Group. Bold P-values are significant according to the threshold P<0.05.
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95% CI
Synchronous SBRT
95% CI
Metachronous 95% CI Surgery + SBRT 95% CI SBRT
3-Year OS Rate
54.2%
48.8– 59.3%
46.4%
19.3– 69.9%
79.7%*
64.4– 88.9%
95.4%*
89.2– 98.0%
3-Year FFP Rate
67.3%
60.9– 72.9%
57.5%
25.3– 80.0%
85.8%
70.7– 93.5%
95.4%*
89.2– 98.0%
3-Year Local Control Rate
89.4%
85.3– 93.5%
75.0%
53.8– 96.2%
96.0%
90.3– 100%
98.2%*
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Single SBRT
95.8%– 100%
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Table 2: Clinical Outcomes. * means a statistical difference when compared to the single SBRT cohort.
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Pneumonitis
7
Brachial Plexopathy Bronchial obstruction Dermatitis
36
2
12
4
1
1
11 1
1
3 5
4
1
1
1
2
Pleural Effusion
1
SBRT + Surgery n=108 patients 1 2 3 4 5 15
1
1
3 10
1 4
1
1
1
1
1
2
1
2
1
3
1
14 3.5% 124 29.4% -
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3
1
Hemoptysis
Severe (Grade≥3) % of patients Significance P-value Overall % of patients Significance P-value
3
2
Esophagitis
Other
1
Metachronous n=48 patients 1 2 3 4 5
RI PT
Chest Wall 39
Synchronous n=14 patients 1 2 3 4 5
SC
Grade*
Single n=374 patients 1 2 3 4 5
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2 14.3% n.s. 0.10 8 50% n.s. 0.14
2 4.2% n.s. 0.68 24 37.5% n.s. 0.24
6 5.6% n.s. 0.40 38 33.3% n.s. 0.48
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Table 3: SBRT-related toxicity in each group. *Toxicities were graded according to the Common Terminology Criteria for Adverse Events. Analysis was performed using two-sided Fisher’s exact tests between the single treatment group and each of the other three groups (n.s.; not significant).
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Figure 1: Consort diagram.
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****
RI PT
****
Patients at risk
14 48 108
6 mo. 371 14 48 108
12 mo. 329 13 48 108
18 mo. 286 11 48 107
24 mo. 249 6 45 107
30 mo. 208 6 41 105
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Single Syn Meta Surg+SBRT
0 mo. 374
SC
n.s.
36 mo. 163 6 32 103
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Figure 2: Overall survival for each group. Kaplan-Meier survival analysis was performed followed by Wilcoxon tests comparing each group to the single SBRT treatment group (n.s.; not significant, ****P<0.0001).
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****
RI PT
*
Patients at risk 0 mo. 374 14 48 108
6 mo. 334 12 47 108
12 mo. 254 8 45 107
18 mo. 209 5 42 105
24 mo. 173 3 39 104
30 mo. 133 3 30 102
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Single Syn Meta Surg+SBRT
SC
n.s.
36 mo. 89 3 25 99
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Figure 3: Freedom from progression for each group. Kaplan-Meier survival analysis was performed followed by Wilcoxon tests comparing each group to the single SBRT treatment group (n.s.; not significant, *P<0.05, ****P<0.0001).
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** n.s.
0.8
Single SBRT Synchronous SBRT Metachronous SBRT Surgery + SBRT …
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n.s.
0.4
Tumors at risk Single Syn Meta Surg+SBRT
0.2
6 mo. 341 26 72 125
12 mo. 270 18 64 122
0.0 0
6
12
18
18 mo. 221 10 59 118
24 mo. 183 6 51 115
30 mo. 142 6 41 109
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0 mo. 373 27 84 127
SC
0.6
24
30
36 mo. 101 6 35 106 36
Time Since Start of Treatment (months)
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Figure 4: Local control for tumors treated with SBRT in each group. Kaplan-Meier survival analysis was performed followed by Wilcoxon tests comparing each group to the single SBRT treatment group (n.s.; not significant, **P<0.01).
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Cumulative Local Control Rate
1.0
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A
n.s. n.s.
1 .0
Single SBRT Synchronous SBRT Metachronous SBRT Surgery + SBRT
0 .8
RI PT
…
0 .6
0 .4
Single Syn Meta Surg+SBRT
0 .2
6 mo. 328 12 47 97
0 .0 0
6
12
Patients at risk 12 mo. 18 mo. 261 218 9 5 46 43 81 75
SC
0 mo. 373 13 47 107
24 mo. 179 4 40 63
30 mo. 137 4 31 53
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Cumulative Freedom from Pneumonitis
n.s.
18
24
36 mo. 98 4 26 44
30
36
Time Since Start of Treatment (months)
B
…
EP
0.6
Single SBRT Synchronous SBRT Metachronous SBRT Surgery + SBRT
n.s. n.s. n.s.
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0.8
0.4
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Cumulative Freedom from Chest Wall Toxicity
1.0
0 mo. 373 13 47 107
Single Syn Meta Surg+SBRT
0.2
Patients at risk 6 mo. 326 12 45 98
12 mo. 232 7 39 77
18 mo. 182 4 35 70
24 mo. 142 3 32 62
30 mo. 103 3 24 52
36 mo. 69 3 20 44
0.0 0
6
12
18
24
30
36
Time Since Start of Treatment (months)
Figure 5: Freedom from pneumonitis (A) and chest wall toxicity (B). Kaplan-Meier survival analysis was performed followed by Wilcoxon tests comparing each group to the single SBRT treatment group (n.s.; not significant).