Original Study
Classification and Reporting of Late Radiographic Changes After Lung Stereotactic Body Radiotherapy: Proposing a New System Hamid Raziee,1 Andrew Hope,1 Salman Faruqi,1 Mei Ling Yap,1 Heidi Roberts,2 Sonja Kandel,2 Lisa W. Le,3 Anthony Brade,1 John Cho,1 Alex Sun,1 Andrea Bezjak,1 Meredith E. Giuliani1 Abstract Radiation-induced parenchymal lung changes after stereotactic body radiotherapy are common, and can obscure the primary tumor site. In this study we propose a structured radiographic reporting tool for characterization of these changes, pilot its feasibility in a group of radiation oncologists, and test the interrater agreement. We could demonstrate the applicability of the scale, with a fair to moderate agreement. Background: The purpose of the study was to design and pilot a synoptic scale for characterization of late radiographic changes after lung stereotactic body radiotherapy (SBRT). Patients and Methods: A participatory design process involving 6 radiation oncologists and 2 thoracic radiologists was used in the scale’s design. Seventy-seven early-stage nonesmall-cell lung cancer patients who were treated with SBRT were included, and after treatment their serial computed tomography (CT) images were scored by 6 radiation oncologists. Gwet’s First-order Agreement Coefficient (AC1) and a leave-one-out (LOO) analysis was used to assess interrater reliability and variability among raters, respectively. Results: The scale reports on 5 independent categories including “tumor in primary site,” “tumor in involved lobe,” “consolidation,” “volume loss,” and “ground-glass or interstitial changes.” At each time point, each category is reported as “increased,” “stable,” “decreased,” “obscured,” or “not present,” compared with the previous. The total number of rated images for the pilot ranged from 450 at 6 months to 84 at 48 months. The primary tumor site was scored as obscured in 38% to 40% of ratings from 12 months onward; 3% to 5% of primary tumors were scored as “increased.” Consolidation, volume loss, and ground-glass or interstitial changes were increasingly marked as “stable” with time. At 24 months, AC1 was 0.28 (LOO, 0.22-0.42), 0.47 (LOO, 0.39-0.72), 0.45 (LOO, 0.42-0.50), 0.21 (LOO, 0.15-0.26), and 0.25 (LOO, 0.20-0.38) for the 5 categories listed, respectively. Conclusion: In a population of clinicians, this scale could be implemented to characterize evolving lung changes after SBRT, and had fair to moderate interrater agreement. Obscured tumor site is a common challenge of follow-up CT imaging, and new imaging techniques should be explored. This scale provides a tool for communicating changes after SBRT. Clinical Lung Cancer, Vol. 16, No. 6, e245-51 ª 2015 Elsevier Inc. All rights reserved. Keywords: Lung cancer, Postradiation lung fibrosis, Radiological changes, SBRT, Synoptic reporting
Introduction 1
Radiation Medicine Program, Department of Radiation Oncology, Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada 2 Department of Medical Imaging, University of Toronto, Women’s College Hospital, Toronto, Ontario, Canada 3 Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Ontario, Canada Submitted: Apr 2, 2015; Revised: May 21, 2015; Accepted: May 26, 2015; Epub: June 02, 2015 Address for correspondence: Meredith E. Giuliani, MBBS, MEd, FRCPC, Department of Radiation Oncology, 610 University Ave, 5th Floor, Princess Margaret Cancer Centre, Toronto, Ontario M5G 2M9, Canada Fax: 416-946-6561; e-mail contact: [email protected]
1525-7304/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2015.05.008
Stereotactic body radiotherapy (SBRT) uses precise methods of tumor localization to deliver high and ablative radiation doses to tumors in few fractions, and avoids normal surrounding tissues. This technique has demonstrated more than a 90% 3-year local control rate for early-stage inoperable nonesmall-cell lung cancer (NSCLC),1-3 and is currently the standard of care for this group of patients.4-6 Because of its high efficacy and safety, it has also been proposed for use in younger and healthier operable patients.7-9 Radiation causes damage in healthy lung parenchyma. The pattern of radiation-induced lung injury (RILI) after SBRT is
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Characterizing Late Radiographic Changes After Lung SBRT Table 1 Radiographic Scoring Scale Scoring Category Tumor in Primary Site Tumor in Involved Lobe Consolidationa Volume Lossb Ground-Glassc or Interstitial Changesd
Changes After SBRT Increased Increased Increased Increased Increased
Stable Stable Stable Stable Stable
Decreased Decreased Decreased NA Decreased
Not Not Not Not Not
present present present present present
Obscured Obscured NA NA NA
At each time point, images are compared to the CT scanat the previous time point and scored according to this scale. Abbreviation: SBRT ¼ stereotactic body radiotherapy. a Soft tissue density obscuring the underlying lung anatomy, separate from the tumor. b Decreased volume of the tissue in question, associated with retraction of the underlying anatomy. c Increased lung density, the underlying anatomy is still visible. d Thickening of the existing lung interstitium.
qualitatively different from changes after conventional radiotherapy, perhaps because of the higher dose per fraction and greater delivered biologically-effective radiation dose.10 Radiation-induced changes
are common,11 and start soon after treatment with a 30% incidence of patchy consolidation or ground-glass density at 3 months,12 and demonstrate evolution in appearance for several years after
Figure 1 Radiographic Changes in 4 Patients: ‘Obscured’ ‘Tumor in Primary Site’ in (B) (18 Months After Stereotactic Body Radiotherapy [SBRT]) Compared With (A) (Before SBRT); ‘Increased’ ‘Consolidation’ in (D) (6 Months After SBRT) Compared With (C) (3 Months After SBRT); ‘Increased’ ‘Volume Loss’ in (F) (6 Months After SBRT) Compared With (E) (3 Months After SBRT)
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Hamid Raziee et al radiation.13,14 They might obscure the primary tumor site, create challenge in differentiating local recurrence from benign fibrosis, and therefore lead to either unnecessary investigations or missed opportunities for salvage. Lung SBRT studies and current clinical practice rely on thorax computed tomography (CT) scan as the principal follow-up method after treatment, and Response Evaluation Criteria in Solid Tumors (RECIST) criteria are commonly used for evaluation of tumor response. Local failure, according to RECIST criteria, is defined as at least 20% increase in the longest diameter of the gross tumor volume on CT scan.15 However, this tool has shown a high false positive rate and a low positive predictive value (PPV) for detection of recurrence, mostly because of RILI and fibrosis confounding the assessment of change in the primary tumor.16 In addition, tools to facilitate clear communication among clinicians of radiological changes after SBRT, particularly between radiologists and radiation oncologists, are lacking. Structured and synoptic reporting improves the communication of radiological findings and affects physicians’ interpretation of reports.17 Breast Imaging Reporting and Data Systems (BI-RADS) is a familiar example, which improved communication and reduced variability in reporting.18 Structured and synoptic reporting systems are in use in operative notes, and have been widely adopted for pathology reporting.19,20 The purpose of this study was to use a multidisciplinary approach to design a structured radiographic scoring and reporting system for long-term lung changes after SBRT, and to pilot its feasibility and practical applicability in a group of lung radiation oncologists in one institution. We also evaluated the agreement between raters.
Clinical data such as age, sex, radiation dose, patterns of recurrence, and imaging frequency were extracted from the prospective database. Patients with multiple courses of radiotherapy, metastatic lung tumors, or multiple synchronous primary tumors were excluded. Patients with local recurrence, either detected using imaging or biopsy-proven were included. This study was performed with research ethics board approval. Staging before SBRT was done using CT scans of the thorax, positron emission tomography/CT scan, and brain magnetic resonance imaging or CT scan. Pathological diagnosis was obtained where possible. Patients were treated according to the institutional SBRT protocol, mostly with 1 of 3 dose regiments; 48 Gy in 4 fractions (12 Gy per fraction delivered every other day) for peripheral tumors 3 cm, 54 Gy in 3 fractions (18 Gy per fraction delivered every other day) for peripheral tumors > 3 cm, or 60 Gy in 8 fractions (7.5 Gy per fraction delivered once per day) for central tumors.3 Radiation was delivered using step-and-shoot intensitymodulated radiation therapy in all patients except 1 who received volumetric arc therapy. Patient follow-up included a chest x-ray 6 weeks after SBRT, followed with thorax CT scans at 3, 6, 12, 18, and 24 months, and then annually.
Scale Piloting Video clips were prepared from axial slices of diagnostic thorax CT scans at baseline (before treatment) and after treatment at 6, 12, 18, 24, 36, and 48 months. Images were anonymized and clinicians were blinded to clinical outcomes. Videos were presented to the group of 6 lung radiation oncologists. For each time point, the current, the previous, and the baseline video clips were played simultaneously. Each rater independently scored radiographic changes on a standardized form, using the scale.
Patients and Methods Scale Development We used a participatory design process21 that involved a team of 6 lung radiation oncologists and 2 thoracic radiologists, to develop a synoptic scale for reporting radiological changes after SBRT (Table 1). The scale was designed to comprehensively capture radiographic changes in the primary tumor and the surrounding lung parenchyma. Categories for scoring were: (1) tumor in primary site; (2) tumor in involved lobe; (3) consolidation; (4) volume loss; and (5) ground-glass or interstitial changes. “Tumor in primary site” was used to represent any mass in the initial place where the primary tumor was located. Presence of mass elsewhere in the lobe containing the primary tumor was categorized under “tumor in involved lobe.” To account for evolution of radiological changes, each category was scored in comparison with the previous thorax CT scan, and was characterized as ‘increased,’ ‘stable,’ ‘decreased,’ ‘obscured,’ or ‘not present’ (Figure 1). Some identifiers were not applicable to some categories (Table 1).
Patient Selection Patients with T1 to 2 N0 M0 NSCLC who had received lung SBRT from May 2004 to January 2012 and had a minimum of 6 months of follow-up after SBRT with available thorax CT scans were included from a prospective database. This database contains information on patient demographic characteristics, treatment, toxicities, patterns of recurrence, and cause of death.
Table 2 Patient Characteristics (n [ 77) Characteristic Age, Years
Value (%) Median, 74 (range, 52-90)
Sex Male
35 (45)
Female
42 (55)
Fractionation (Gy/Fractions) 48/4
45 (58)
60/8
9 (12)
60/3
6 (8)
54/3
14 (18)
50/10
3 (4)
T Stage T1
56 (71)
T2
21 (29)
Histology Adenocarcinoma
31 (40)
Squamous
13 (17)
Large cell
3 (4)
NSCLC NOS
11 (14)
No biopsy/inconclusive
19 (25)
Values are presented as n (%) except where otherwise stated. Abbreviation: NSCLC NOS ¼ nonesmall-cell lung cancer not otherwise specified.
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Characterizing Late Radiographic Changes After Lung SBRT Figure 2 Time-Trend Analysis of Ratings for Each Scale Category. (A) Tumor in Primary Site; (B) Tumor in Involved Lobe; (C) Consolidation; (D) Volume Loss; and (E) Ground-Glass or Interstitial Changes. Vertical Axis Demonstrates the Percentage of Scores at Each Time Point
Analysis The proportion of patients in each category at each time point was determined. Percent agreement between raters was calculated for each time point. Gwet’s First-order Agreement Coefficient (AC1)22 was used to establish interrater reliability at each time point on each subset of the scale. This statistical method provides the ability to adjust for unbalanced distribution of rating among different data categories, and can be used in multirater and multicategory settings. The strength of agreement is based on ranges: 00.2, slight; 0.2-0.4, fair; 0.4-0.6, moderate; 0.6-0.8, strong; and
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0.8-1.0, almost perfect.23 Leave-one-out (LOO) analysis was performed on each rater to calculate AC1 score sensitivity to individual raters.
Results Seventy-seven patients were included (Table 2). The median follow-up was 28 months (range, 6-108 months), during which 7 documented local recurrences were detected, 5 of which were biopsy-proven. There were 75, 67, 52, 47, 31, and 14 image sets available at 6, 12, 18, 24, 36, and 48 months, respectively. At each
Hamid Raziee et al “Volume loss” and “ground-glass or interstitial changes” showed a pattern of stability at 18 and 24 months, respectively, similar to consolidation. They were present in 58% and 70% of cases at 48 months, respectively (Figure 2). The results of interrater reliability (AC1) and LOO analysis demonstrated fair to moderate agreement between raters, with particularly greater agreement for the “consolidation” and “tumor in involved lobe” categories, with a range of 0.31 to 0.53 and 0.44 to 0.53 over different time intervals, respectively. LOO analysis demonstrated considerable variation in AC1 range. At 24 months for instance, LOO ranged between 0.22 to 0.42 for “tumor in primary site,” 0.39 to 0.72 for “tumor in involved lobe,” 0.42 to 0.50 for “consolidation,” 0.15 to 0.26 for “volume loss,” and 0.20 to 0.38 for “ground-glass changes” (Table 3).
Figure 3 Temporal Changes of Selected Radiologic Scoring Scale Scores
Discussion In the present study, we proposed a radiographic synoptic scale for characterization of long-term changes in primary tumor site and surrounding lung parenchyma after SBRT for early-stage lung cancer. We designed this scale with participation of thoracic radiologists and radiation oncologists, and piloted its feasibility and reliability in a cohort of radiation oncologists using follow-up thoracic CT images of treated patients. Characterization and timing of lung changes after SBRT is important in differentiating RILI from recurrence. To categorize RILI, Koening classification is the only available scoring system. It was initially designed for lung changes after Three-dimensional Conformal Radiotherapy (3-DCRT), and was later adapted to late RILI after SBRT.11,12,24 It provides for stratification of radiationinduced radiographic changes into 3 groups of “modified conventional pattern,” “mass-like fibrosis,” and “scar-like fibrosis.”25 In this system, consolidation, volume loss, and traction bronchiectasis are grouped under one category of “modified conventional pattern.” Consolidation surrounding the tumor is classified as “mass-like” change, and linear opacities close to treatment volume are called “scar-like fibrosis.” This scale does not allow for evolving changes over time, and has shown modest interrater reliability.14 Application of this system as a tool to communicate changes after SBRT between clinicians or to report radiological changes has been limited, perhaps because of overinclusion of radiological changes in one category, and underinclusion in others, which leads to various interpretations. The variability of the “modified conventional”
time point, there were patients who had missed undergoing the corresponding imaging, or who were lost to follow-up. Therefore, 286 CT images were reviewed in total, each image set corresponding to 1 tumor time point, and 8580 scorings were done for all categories. “Tumor in primary site” was scored as “increased” in 3% to 5% of ratings, and was increasingly marked as “obscured” and reached a peak of 43% at 24 months (Figure 2). “Obscured” primary tumor site scores started to increase coincidental with or soon after “consolidation,” “ground-glass or interstitial changes,” and “volume loss,” which reached their peaks in receipt of “increased” scores (Figure 3). “Tumor in primary site” was “present” in 77% at 48 months, and decreased from 85% at 6 months (Figure 2). “Consolidation” scores showed a trend toward stability after 24 months, with fewer cases marked as “increased” and more cases identified as “stable” at each time point from 6 to 24 months (Figure 2). Over time, the proportion of cases in which “consolidation” was scored as “present” increased, from 68% at 6 months to 86% at 48 months.
Table 3 AC1 Scores and LOO Analysis for Inter-Rater Reliability Tumor in Primary Site
Tumor in Involved Lobe
Ground-Glass or Interstitial Changes
Time Interval, Months
AC1
LOO Range
AC1
LOO Range
AC1
LOO Range
AC1
LOO Range
AC1
LOO Range
6 12 18 24 36 48
0.28 0.31 0.28 0.28 0.25 0.26
0.24-0.44 0.28-0.46 0.23-0.40 0.22-0.42 0.22-0.36 0.21-0.39
0.53 0.46 0.47 0.47 0.45 0.44
0.47-0.71 0.39-0.69 0.39-0.72 0.39-0.72 0.39-0.68 0.35-0.67
0.53 0.41 0.31 0.45 0.40 0.40
0.48-0.62 0.38-0.46 0.29-0.37 0.42-0.50 0.36-0.53 0.35-0.52
0.52 0.31 0.25 0.21 0.22 0.22
0.47-0.65 0.27-0.37 0.20-0.32 0.15-0.26 0.17-0.30 0.18-0.28
0.33 0.24 0.18 0.25 0.25 0.32
0.29-0.38 0.19-0.33 0.14-0.31 0.20-0.38 0.19-0.42 0.25-0.45
Consolidation
Volume Loss
Abbreviation: LOO ¼ leave-one-out, AC1 ¼ First-order Agreement Coefficient.
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Characterizing Late Radiographic Changes After Lung SBRT proportion in different series can further illustrate this fact. Trovo et al found a 44% modified conventional pattern at 13 to 18 months after SBRT.12 In the study by Dahele et al, the same pattern was seen in 71% of images around the same time,11 and in the most recent study by Faruqi et al, this pattern was seen in approximately 52% of images after 12 months.14 Part of this discordance could also be because of unclear definition of categories. To fill this gap, our proposed radiographic reporting system has some advantages that make it a candidate for clinical application to facilitate the communication of RILI. First, it captures changes in the primary tumor site and the surrounding lung. Therefore, it can offer a more comprehensive account of radiological changes compared with RECIST, which defines primary tumor changes only, and modified Koening scale, which exclusively describes parenchymal changes. Second, it uses well defined and familiar radiographic patterns and 1 descriptor per category, and therefore is easy to use, to score, and to implement. Third, it allows for definition of changes in each category compared with the previous imaging, to account for the evolving and dynamic nature of RILI changes. When piloted in a cohort of chest radiation oncologists, the cumulative scoring demonstrated increased consolidation, volume loss, and ground-glass and interstitial changes in most patients, particularly for the first 18 to 24 months. This is similar to previous reports.11,14 However, our scale showed fair to moderate interrater agreement in all categories, which was not unexpected. In a previous study on the same clinician participants with the same methodology, the interrater reliability scores of the modified Koening scale were in a range similar to our proposed scale.14 In addition, less than perfect agreement on lung parenchymal CT changes has been reported, when the interobserver agreement between thoracic radiologists for the diagnosis of diffuse parenchymal lung disease was moderate,26,27 with weighted k of 0.42 and 0.48, respectively. The low rate of agreement between raters in our study seemed to originate mainly from the variability in defining patterns, which seems to be inherent to this imaging modality. Also, we tested the agreement of a clinician cohort on radiographic patterns. Perhaps a greater agreement might be achievable among radiologists. In our study, LOO analysis showed changes in agreement scores across all categories, which shows that increased familiarity with the scale and standardization of terminology could improve agreement. An important finding in our study was the high rate of “obscured” scores for “tumor in primary site.” Obscured primary site negatively affects the ability to visualize the previously described high-risk features for recurrence, including enlarging opacity, bulging margins, craniocaudal growth, and air-bronchogram loss.16,28,29 RECIST, which is the standard criteria for characterization of tumor regrowth can also be affected by the obscuring effect, hence, the low PPV, which potentially leads to a high rate of false positive results for diagnosis of local failure.16 The strength of this study is a multidisciplinary approach to design a scale that accounts for temporal changes after SBRT, and use of familiar radiological terms that are easy to use and understand. In addition, we could demonstrate the feasibility of its use in a group of expert clinicians. This study has some limitations as well. First, to reduce bias, we blinded clinicians to clinical
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details and asked them to score in isolation without consultation with others. However, the option for consultation and the availability of clinical information in real cases might increase agreement. Second, we focused on experts in one institution who share a common institutional practice. Expansion of this study beyond one institution and testing of interrater reliability with radiologists would reproduce standard clinical practice more closely. Finally, because of the favorable outcomes of SBRT, we had few proven recurrences, and therefore, cannot establish any meaningful relevance of our system to prediction of local recurrence at this time. With longer follow-up, this analysis might become feasible in the future. We believe that the scale is applicable and useful in daily clinical practice, particularly for communication of radiological changes between clinicians and radiologists. Its multicategory nature is fundamental to individual characterization of each type of change. It is hoped that with clarification of each category’s definition and pattern, interrater agreement would increase (training effect). For instance, a guidance document with definitions and examples of changes would potentially increase agreement.
Conclusion In this study we proposed a new radiographic reporting system for CT changes after SBRT that is applicable to clinical practice for communication of changes, and is easy to implement. It demonstrated fair to moderate interrater reliability, similar to the previous scale. This system can be used to facilitate reporting and communication of CT scan findings in clinical follow-up of SBRT patients.
Clinical Practice Points Stereotactic radiotherapy has shown promise in the treatment of
early stage NSCLC, and is the standard of care for inoperable patients. Lung parenchymal changes after stereotactic radiation are common, affect the visualization of the primary tumor site, and potentially hinder the ability to use standard RECIST tumor response criteria to assess recurrence. Previously reported scales for characterization of these radiographic changes are not currently in clinical use for communication of these changes, and are not used for reporting radiological findings. We propose a synoptic system for definition of lung changes after SBRT, in which each radiographic pattern is reported in comparison with the previous imaging time point. The results of this pilot test of the proposed scale on a cohort of radiation oncologists shows its applicability for clinical use, with similar trends of radiographic changes and interrater agreement compared with the previous scales.
Acknowledgments This study was supported by the Academic Enrichment Fund of the Radiation Medicine Program,University of Toronto. The funding source had no role in study design, data collection, analysis, or interpretation; in the writing of the manuscript; and in the decision to submit for publication.
Hamid Raziee et al Disclosure Drs Bezjak, Hope, and Giuliani have received travel funding from Elekta and Dr Bezjak has received program funding from Elekta in the past. The remaining authors have stated that they have no conflicts of interest.
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13. 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. Radiother Oncol 2007; 85:435-42. 14. Faruqi S, Giuliani ME, Raziee H, et al. Interrater reliability of the categorization of late radiographic changes after lung stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys 2014; 89:1076-83. 15. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47. 16. Dunlap NE, Yang WS, McIntosh A, et al. Computed tomography-based anatomic assessment overestimates local tumor recurrence in patients with mass-like consolidation after stereotactic body radiotherapy for early-stage nonesmall-cell lung cancer. Int J Radiat Oncol Biol Phys 2012; 84:1071-7. 17. Schwartz LH, Panicek DM, Berk AR, Li Y, Hricak H. Improving communication of diagnostic radiology findings through structured reporting. Radiology 2011; 260: 174-81. 18. Burnside ES, Sickles EA, Bassett LW, et al. The ACR BI-RADS experience: learning from history. J Am Coll Radiol 2009; 6:851-60. 19. Leslie KO, Rosai J. Standardization of the surgical pathology report: formats, templates, and synoptic reports. Semin Diagn Pathol 1994; 11:253-7. 20. Markel SF, Hirsch SD. Synoptic surgical pathology reporting. Hum Pathol 1991; 22:807-10. 21. Kensing F, Blomberg J. Participatory design: issues and concerns. Comput Support 1998; 7:167-85. 22. Gwet KL. Computing inter-rater reliability and its variance in the presence of high agreement. Br J Math Stat Psychol 2008; 61:29-48. 23. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977; 33:159-74. 24. Kimura T, Matsuura K, Murakami Y, et al. CT appearance of radiation injury of the lung and clinical symptoms after stereotactic body radiation therapy (SBRT) for lung cancers: are patients with pulmonary emphysema also candidates for SBRT for lung cancers? Int J Radiat Oncol Biol Phys 2006; 66: 483-91. 25. Koenig TR, Munden RF, Erasmus JJ, et al. Radiation injury of the lung after three-dimensional conformal radiation therapy. Am J Roentgenol 2002; 178: 1383-8. 26. Antunes VB, Meirelles GS, Jasinowodolinski D, et al. Observer agreement in the diagnosis of interstitial lung diseases based on HRCT scans. J Bras Pneumol 2010; 36:29-36. 27. Aziz ZA, Wells AU, Hansell DM, et al. HRCT diagnosis of diffuse parenchymal lung disease: inter-observer variation. Thorax 2004; 59:506-11. 28. Huang K, Dahele M, Senan S, et al. Radiographic changes after lung stereotactic ablative radiotherapy (SABR) - can we distinguish recurrence from fibrosis? A systematic review of the literature. Radiother Oncol 2012; 102: 335-42. 29. Huang K, Senthi S, Palma DA, et al. High-risk CT features for detection of local recurrence after stereotactic ablative radiotherapy for lung cancer. Radiother Oncol 2013; 109:51-7.
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Classification and Reporting of Late Radiographic Changes After Lung Stereotactic Body Radiotherapy: Proposing a New System Hamid Raziee,1 Andrew Hope,1 Salman Faruqi,1 Mei Ling Yap,1 Heidi Roberts,2 Sonja Kandel,2 Lisa W. Le,3 Anthony Brade,1 John Cho,1 Alex Sun,1 Andrea Bezjak,1 Meredith E. Giuliani1 Abstract Radiation-induced parenchymal lung changes after stereotactic body radiotherapy are common, and can obscure the primary tumor site. In this study we propose a structured radiographic reporting tool for characterization of these changes, pilot its feasibility in a group of radiation oncologists, and test the interrater agreement. We could demonstrate the applicability of the scale, with a fair to moderate agreement. Background: The purpose of the study was to design and pilot a synoptic scale for characterization of late radiographic changes after lung stereotactic body radiotherapy (SBRT). Patients and Methods: A participatory design process involving 6 radiation oncologists and 2 thoracic radiologists was used in the scale’s design. Seventy-seven early-stage nonesmall-cell lung cancer patients who were treated with SBRT were included, and after treatment their serial computed tomography (CT) images were scored by 6 radiation oncologists. Gwet’s First-order Agreement Coefficient (AC1) and a leave-one-out (LOO) analysis was used to assess interrater reliability and variability among raters, respectively. Results: The scale reports on 5 independent categories including “tumor in primary site,” “tumor in involved lobe,” “consolidation,” “volume loss,” and “ground-glass or interstitial changes.” At each time point, each category is reported as “increased,” “stable,” “decreased,” “obscured,” or “not present,” compared with the previous. The total number of rated images for the pilot ranged from 450 at 6 months to 84 at 48 months. The primary tumor site was scored as obscured in 38% to 40% of ratings from 12 months onward; 3% to 5% of primary tumors were scored as “increased.” Consolidation, volume loss, and ground-glass or interstitial changes were increasingly marked as “stable” with time. At 24 months, AC1 was 0.28 (LOO, 0.22-0.42), 0.47 (LOO, 0.39-0.72), 0.45 (LOO, 0.42-0.50), 0.21 (LOO, 0.15-0.26), and 0.25 (LOO, 0.20-0.38) for the 5 categories listed, respectively. Conclusion: In a population of clinicians, this scale could be implemented to characterize evolving lung changes after SBRT, and had fair to moderate interrater agreement. Obscured tumor site is a common challenge of follow-up CT imaging, and new imaging techniques should be explored. This scale provides a tool for communicating changes after SBRT. Clinical Lung Cancer, Vol. 16, No. 6, e245-51 ª 2015 Elsevier Inc. All rights reserved. Keywords: Lung cancer, Postradiation lung fibrosis, Radiological changes, SBRT, Synoptic reporting
Introduction 1
Radiation Medicine Program, Department of Radiation Oncology, Princess Margaret Cancer Center, University of Toronto, Toronto, Ontario, Canada 2 Department of Medical Imaging, University of Toronto, Women’s College Hospital, Toronto, Ontario, Canada 3 Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, Ontario, Canada Submitted: Apr 2, 2015; Revised: May 21, 2015; Accepted: May 26, 2015; Epub: June 02, 2015 Address for correspondence: Meredith E. Giuliani, MBBS, MEd, FRCPC, Department of Radiation Oncology, 610 University Ave, 5th Floor, Princess Margaret Cancer Centre, Toronto, Ontario M5G 2M9, Canada Fax: 416-946-6561; e-mail contact: [email protected]
1525-7304/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2015.05.008
Stereotactic body radiotherapy (SBRT) uses precise methods of tumor localization to deliver high and ablative radiation doses to tumors in few fractions, and avoids normal surrounding tissues. This technique has demonstrated more than a 90% 3-year local control rate for early-stage inoperable nonesmall-cell lung cancer (NSCLC),1-3 and is currently the standard of care for this group of patients.4-6 Because of its high efficacy and safety, it has also been proposed for use in younger and healthier operable patients.7-9 Radiation causes damage in healthy lung parenchyma. The pattern of radiation-induced lung injury (RILI) after SBRT is
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Characterizing Late Radiographic Changes After Lung SBRT Table 1 Radiographic Scoring Scale Scoring Category Tumor in Primary Site Tumor in Involved Lobe Consolidationa Volume Lossb Ground-Glassc or Interstitial Changesd
Changes After SBRT Increased Increased Increased Increased Increased
Stable Stable Stable Stable Stable
Decreased Decreased Decreased NA Decreased
Not Not Not Not Not
present present present present present
Obscured Obscured NA NA NA
At each time point, images are compared to the CT scanat the previous time point and scored according to this scale. Abbreviation: SBRT ¼ stereotactic body radiotherapy. a Soft tissue density obscuring the underlying lung anatomy, separate from the tumor. b Decreased volume of the tissue in question, associated with retraction of the underlying anatomy. c Increased lung density, the underlying anatomy is still visible. d Thickening of the existing lung interstitium.
qualitatively different from changes after conventional radiotherapy, perhaps because of the higher dose per fraction and greater delivered biologically-effective radiation dose.10 Radiation-induced changes
are common,11 and start soon after treatment with a 30% incidence of patchy consolidation or ground-glass density at 3 months,12 and demonstrate evolution in appearance for several years after
Figure 1 Radiographic Changes in 4 Patients: ‘Obscured’ ‘Tumor in Primary Site’ in (B) (18 Months After Stereotactic Body Radiotherapy [SBRT]) Compared With (A) (Before SBRT); ‘Increased’ ‘Consolidation’ in (D) (6 Months After SBRT) Compared With (C) (3 Months After SBRT); ‘Increased’ ‘Volume Loss’ in (F) (6 Months After SBRT) Compared With (E) (3 Months After SBRT)
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Hamid Raziee et al radiation.13,14 They might obscure the primary tumor site, create challenge in differentiating local recurrence from benign fibrosis, and therefore lead to either unnecessary investigations or missed opportunities for salvage. Lung SBRT studies and current clinical practice rely on thorax computed tomography (CT) scan as the principal follow-up method after treatment, and Response Evaluation Criteria in Solid Tumors (RECIST) criteria are commonly used for evaluation of tumor response. Local failure, according to RECIST criteria, is defined as at least 20% increase in the longest diameter of the gross tumor volume on CT scan.15 However, this tool has shown a high false positive rate and a low positive predictive value (PPV) for detection of recurrence, mostly because of RILI and fibrosis confounding the assessment of change in the primary tumor.16 In addition, tools to facilitate clear communication among clinicians of radiological changes after SBRT, particularly between radiologists and radiation oncologists, are lacking. Structured and synoptic reporting improves the communication of radiological findings and affects physicians’ interpretation of reports.17 Breast Imaging Reporting and Data Systems (BI-RADS) is a familiar example, which improved communication and reduced variability in reporting.18 Structured and synoptic reporting systems are in use in operative notes, and have been widely adopted for pathology reporting.19,20 The purpose of this study was to use a multidisciplinary approach to design a structured radiographic scoring and reporting system for long-term lung changes after SBRT, and to pilot its feasibility and practical applicability in a group of lung radiation oncologists in one institution. We also evaluated the agreement between raters.
Clinical data such as age, sex, radiation dose, patterns of recurrence, and imaging frequency were extracted from the prospective database. Patients with multiple courses of radiotherapy, metastatic lung tumors, or multiple synchronous primary tumors were excluded. Patients with local recurrence, either detected using imaging or biopsy-proven were included. This study was performed with research ethics board approval. Staging before SBRT was done using CT scans of the thorax, positron emission tomography/CT scan, and brain magnetic resonance imaging or CT scan. Pathological diagnosis was obtained where possible. Patients were treated according to the institutional SBRT protocol, mostly with 1 of 3 dose regiments; 48 Gy in 4 fractions (12 Gy per fraction delivered every other day) for peripheral tumors 3 cm, 54 Gy in 3 fractions (18 Gy per fraction delivered every other day) for peripheral tumors > 3 cm, or 60 Gy in 8 fractions (7.5 Gy per fraction delivered once per day) for central tumors.3 Radiation was delivered using step-and-shoot intensitymodulated radiation therapy in all patients except 1 who received volumetric arc therapy. Patient follow-up included a chest x-ray 6 weeks after SBRT, followed with thorax CT scans at 3, 6, 12, 18, and 24 months, and then annually.
Scale Piloting Video clips were prepared from axial slices of diagnostic thorax CT scans at baseline (before treatment) and after treatment at 6, 12, 18, 24, 36, and 48 months. Images were anonymized and clinicians were blinded to clinical outcomes. Videos were presented to the group of 6 lung radiation oncologists. For each time point, the current, the previous, and the baseline video clips were played simultaneously. Each rater independently scored radiographic changes on a standardized form, using the scale.
Patients and Methods Scale Development We used a participatory design process21 that involved a team of 6 lung radiation oncologists and 2 thoracic radiologists, to develop a synoptic scale for reporting radiological changes after SBRT (Table 1). The scale was designed to comprehensively capture radiographic changes in the primary tumor and the surrounding lung parenchyma. Categories for scoring were: (1) tumor in primary site; (2) tumor in involved lobe; (3) consolidation; (4) volume loss; and (5) ground-glass or interstitial changes. “Tumor in primary site” was used to represent any mass in the initial place where the primary tumor was located. Presence of mass elsewhere in the lobe containing the primary tumor was categorized under “tumor in involved lobe.” To account for evolution of radiological changes, each category was scored in comparison with the previous thorax CT scan, and was characterized as ‘increased,’ ‘stable,’ ‘decreased,’ ‘obscured,’ or ‘not present’ (Figure 1). Some identifiers were not applicable to some categories (Table 1).
Patient Selection Patients with T1 to 2 N0 M0 NSCLC who had received lung SBRT from May 2004 to January 2012 and had a minimum of 6 months of follow-up after SBRT with available thorax CT scans were included from a prospective database. This database contains information on patient demographic characteristics, treatment, toxicities, patterns of recurrence, and cause of death.
Table 2 Patient Characteristics (n [ 77) Characteristic Age, Years
Value (%) Median, 74 (range, 52-90)
Sex Male
35 (45)
Female
42 (55)
Fractionation (Gy/Fractions) 48/4
45 (58)
60/8
9 (12)
60/3
6 (8)
54/3
14 (18)
50/10
3 (4)
T Stage T1
56 (71)
T2
21 (29)
Histology Adenocarcinoma
31 (40)
Squamous
13 (17)
Large cell
3 (4)
NSCLC NOS
11 (14)
No biopsy/inconclusive
19 (25)
Values are presented as n (%) except where otherwise stated. Abbreviation: NSCLC NOS ¼ nonesmall-cell lung cancer not otherwise specified.
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Characterizing Late Radiographic Changes After Lung SBRT Figure 2 Time-Trend Analysis of Ratings for Each Scale Category. (A) Tumor in Primary Site; (B) Tumor in Involved Lobe; (C) Consolidation; (D) Volume Loss; and (E) Ground-Glass or Interstitial Changes. Vertical Axis Demonstrates the Percentage of Scores at Each Time Point
Analysis The proportion of patients in each category at each time point was determined. Percent agreement between raters was calculated for each time point. Gwet’s First-order Agreement Coefficient (AC1)22 was used to establish interrater reliability at each time point on each subset of the scale. This statistical method provides the ability to adjust for unbalanced distribution of rating among different data categories, and can be used in multirater and multicategory settings. The strength of agreement is based on ranges: 00.2, slight; 0.2-0.4, fair; 0.4-0.6, moderate; 0.6-0.8, strong; and
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0.8-1.0, almost perfect.23 Leave-one-out (LOO) analysis was performed on each rater to calculate AC1 score sensitivity to individual raters.
Results Seventy-seven patients were included (Table 2). The median follow-up was 28 months (range, 6-108 months), during which 7 documented local recurrences were detected, 5 of which were biopsy-proven. There were 75, 67, 52, 47, 31, and 14 image sets available at 6, 12, 18, 24, 36, and 48 months, respectively. At each
Hamid Raziee et al “Volume loss” and “ground-glass or interstitial changes” showed a pattern of stability at 18 and 24 months, respectively, similar to consolidation. They were present in 58% and 70% of cases at 48 months, respectively (Figure 2). The results of interrater reliability (AC1) and LOO analysis demonstrated fair to moderate agreement between raters, with particularly greater agreement for the “consolidation” and “tumor in involved lobe” categories, with a range of 0.31 to 0.53 and 0.44 to 0.53 over different time intervals, respectively. LOO analysis demonstrated considerable variation in AC1 range. At 24 months for instance, LOO ranged between 0.22 to 0.42 for “tumor in primary site,” 0.39 to 0.72 for “tumor in involved lobe,” 0.42 to 0.50 for “consolidation,” 0.15 to 0.26 for “volume loss,” and 0.20 to 0.38 for “ground-glass changes” (Table 3).
Figure 3 Temporal Changes of Selected Radiologic Scoring Scale Scores
Discussion In the present study, we proposed a radiographic synoptic scale for characterization of long-term changes in primary tumor site and surrounding lung parenchyma after SBRT for early-stage lung cancer. We designed this scale with participation of thoracic radiologists and radiation oncologists, and piloted its feasibility and reliability in a cohort of radiation oncologists using follow-up thoracic CT images of treated patients. Characterization and timing of lung changes after SBRT is important in differentiating RILI from recurrence. To categorize RILI, Koening classification is the only available scoring system. It was initially designed for lung changes after Three-dimensional Conformal Radiotherapy (3-DCRT), and was later adapted to late RILI after SBRT.11,12,24 It provides for stratification of radiationinduced radiographic changes into 3 groups of “modified conventional pattern,” “mass-like fibrosis,” and “scar-like fibrosis.”25 In this system, consolidation, volume loss, and traction bronchiectasis are grouped under one category of “modified conventional pattern.” Consolidation surrounding the tumor is classified as “mass-like” change, and linear opacities close to treatment volume are called “scar-like fibrosis.” This scale does not allow for evolving changes over time, and has shown modest interrater reliability.14 Application of this system as a tool to communicate changes after SBRT between clinicians or to report radiological changes has been limited, perhaps because of overinclusion of radiological changes in one category, and underinclusion in others, which leads to various interpretations. The variability of the “modified conventional”
time point, there were patients who had missed undergoing the corresponding imaging, or who were lost to follow-up. Therefore, 286 CT images were reviewed in total, each image set corresponding to 1 tumor time point, and 8580 scorings were done for all categories. “Tumor in primary site” was scored as “increased” in 3% to 5% of ratings, and was increasingly marked as “obscured” and reached a peak of 43% at 24 months (Figure 2). “Obscured” primary tumor site scores started to increase coincidental with or soon after “consolidation,” “ground-glass or interstitial changes,” and “volume loss,” which reached their peaks in receipt of “increased” scores (Figure 3). “Tumor in primary site” was “present” in 77% at 48 months, and decreased from 85% at 6 months (Figure 2). “Consolidation” scores showed a trend toward stability after 24 months, with fewer cases marked as “increased” and more cases identified as “stable” at each time point from 6 to 24 months (Figure 2). Over time, the proportion of cases in which “consolidation” was scored as “present” increased, from 68% at 6 months to 86% at 48 months.
Table 3 AC1 Scores and LOO Analysis for Inter-Rater Reliability Tumor in Primary Site
Tumor in Involved Lobe
Ground-Glass or Interstitial Changes
Time Interval, Months
AC1
LOO Range
AC1
LOO Range
AC1
LOO Range
AC1
LOO Range
AC1
LOO Range
6 12 18 24 36 48
0.28 0.31 0.28 0.28 0.25 0.26
0.24-0.44 0.28-0.46 0.23-0.40 0.22-0.42 0.22-0.36 0.21-0.39
0.53 0.46 0.47 0.47 0.45 0.44
0.47-0.71 0.39-0.69 0.39-0.72 0.39-0.72 0.39-0.68 0.35-0.67
0.53 0.41 0.31 0.45 0.40 0.40
0.48-0.62 0.38-0.46 0.29-0.37 0.42-0.50 0.36-0.53 0.35-0.52
0.52 0.31 0.25 0.21 0.22 0.22
0.47-0.65 0.27-0.37 0.20-0.32 0.15-0.26 0.17-0.30 0.18-0.28
0.33 0.24 0.18 0.25 0.25 0.32
0.29-0.38 0.19-0.33 0.14-0.31 0.20-0.38 0.19-0.42 0.25-0.45
Consolidation
Volume Loss
Abbreviation: LOO ¼ leave-one-out, AC1 ¼ First-order Agreement Coefficient.
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Characterizing Late Radiographic Changes After Lung SBRT proportion in different series can further illustrate this fact. Trovo et al found a 44% modified conventional pattern at 13 to 18 months after SBRT.12 In the study by Dahele et al, the same pattern was seen in 71% of images around the same time,11 and in the most recent study by Faruqi et al, this pattern was seen in approximately 52% of images after 12 months.14 Part of this discordance could also be because of unclear definition of categories. To fill this gap, our proposed radiographic reporting system has some advantages that make it a candidate for clinical application to facilitate the communication of RILI. First, it captures changes in the primary tumor site and the surrounding lung. Therefore, it can offer a more comprehensive account of radiological changes compared with RECIST, which defines primary tumor changes only, and modified Koening scale, which exclusively describes parenchymal changes. Second, it uses well defined and familiar radiographic patterns and 1 descriptor per category, and therefore is easy to use, to score, and to implement. Third, it allows for definition of changes in each category compared with the previous imaging, to account for the evolving and dynamic nature of RILI changes. When piloted in a cohort of chest radiation oncologists, the cumulative scoring demonstrated increased consolidation, volume loss, and ground-glass and interstitial changes in most patients, particularly for the first 18 to 24 months. This is similar to previous reports.11,14 However, our scale showed fair to moderate interrater agreement in all categories, which was not unexpected. In a previous study on the same clinician participants with the same methodology, the interrater reliability scores of the modified Koening scale were in a range similar to our proposed scale.14 In addition, less than perfect agreement on lung parenchymal CT changes has been reported, when the interobserver agreement between thoracic radiologists for the diagnosis of diffuse parenchymal lung disease was moderate,26,27 with weighted k of 0.42 and 0.48, respectively. The low rate of agreement between raters in our study seemed to originate mainly from the variability in defining patterns, which seems to be inherent to this imaging modality. Also, we tested the agreement of a clinician cohort on radiographic patterns. Perhaps a greater agreement might be achievable among radiologists. In our study, LOO analysis showed changes in agreement scores across all categories, which shows that increased familiarity with the scale and standardization of terminology could improve agreement. An important finding in our study was the high rate of “obscured” scores for “tumor in primary site.” Obscured primary site negatively affects the ability to visualize the previously described high-risk features for recurrence, including enlarging opacity, bulging margins, craniocaudal growth, and air-bronchogram loss.16,28,29 RECIST, which is the standard criteria for characterization of tumor regrowth can also be affected by the obscuring effect, hence, the low PPV, which potentially leads to a high rate of false positive results for diagnosis of local failure.16 The strength of this study is a multidisciplinary approach to design a scale that accounts for temporal changes after SBRT, and use of familiar radiological terms that are easy to use and understand. In addition, we could demonstrate the feasibility of its use in a group of expert clinicians. This study has some limitations as well. First, to reduce bias, we blinded clinicians to clinical
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details and asked them to score in isolation without consultation with others. However, the option for consultation and the availability of clinical information in real cases might increase agreement. Second, we focused on experts in one institution who share a common institutional practice. Expansion of this study beyond one institution and testing of interrater reliability with radiologists would reproduce standard clinical practice more closely. Finally, because of the favorable outcomes of SBRT, we had few proven recurrences, and therefore, cannot establish any meaningful relevance of our system to prediction of local recurrence at this time. With longer follow-up, this analysis might become feasible in the future. We believe that the scale is applicable and useful in daily clinical practice, particularly for communication of radiological changes between clinicians and radiologists. Its multicategory nature is fundamental to individual characterization of each type of change. It is hoped that with clarification of each category’s definition and pattern, interrater agreement would increase (training effect). For instance, a guidance document with definitions and examples of changes would potentially increase agreement.
Conclusion In this study we proposed a new radiographic reporting system for CT changes after SBRT that is applicable to clinical practice for communication of changes, and is easy to implement. It demonstrated fair to moderate interrater reliability, similar to the previous scale. This system can be used to facilitate reporting and communication of CT scan findings in clinical follow-up of SBRT patients.
Clinical Practice Points Stereotactic radiotherapy has shown promise in the treatment of
early stage NSCLC, and is the standard of care for inoperable patients. Lung parenchymal changes after stereotactic radiation are common, affect the visualization of the primary tumor site, and potentially hinder the ability to use standard RECIST tumor response criteria to assess recurrence. Previously reported scales for characterization of these radiographic changes are not currently in clinical use for communication of these changes, and are not used for reporting radiological findings. We propose a synoptic system for definition of lung changes after SBRT, in which each radiographic pattern is reported in comparison with the previous imaging time point. The results of this pilot test of the proposed scale on a cohort of radiation oncologists shows its applicability for clinical use, with similar trends of radiographic changes and interrater agreement compared with the previous scales.
Acknowledgments This study was supported by the Academic Enrichment Fund of the Radiation Medicine Program,University of Toronto. The funding source had no role in study design, data collection, analysis, or interpretation; in the writing of the manuscript; and in the decision to submit for publication.
Hamid Raziee et al Disclosure Drs Bezjak, Hope, and Giuliani have received travel funding from Elekta and Dr Bezjak has received program funding from Elekta in the past. The remaining authors have stated that they have no conflicts of interest.
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