Journal of Thoracic Oncology:
Radiological Changes After Stereotactic Radiotherapy for Stage I Lung Cancer
Dahele, Max MBChB, MSc; Palma, David MD; Lagerwaard, Frank MD, PhD; Slotman, Ben MD, PhD; Senan, Suresh FRCR, PhD
Department of Radiation Oncology, VU University Medical Center, Amsterdam, The Netherlands.
Disclosure: VU University Medical Center has research collaborations with Varian Medical Systems, Palo Alto, CA, BrainLAB AG, Feldkirchen, Germany, and Velocity Medical Solutions, Atlanta, GA. Max Dahele, MBChB, has received travel support from Varian Medical Systems and BrainLAB; Frank Lagerwaard, MD, PhD, has received honoraria from Varian Medical Systems; Ben Slotman, MD, PhD, has received speaker's fees from Varian Medical Systems and BrainLAB; and Suresh Senan, FRCR, PhD, has received speaker's fees from Varian Medical Systems.
Address for correspondence: Dr. Max Dahele, Department of Radiation Oncology, VU University Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands. E-mail: email@example.com
The first two authors contributed equally to this work.
Introduction: Stereotactic body radiation therapy (SBRT) is entering routine clinical use for selected patients with early-stage non-small cell lung cancer. Post-SBRT radiological changes are commonly seen on follow-up computed tomography (CT) imaging and can cause diagnostic dilemmas. The aim of this study is to describe the incidence, radiological severity, and long-term morphology of these changes.
Methods: CT scans from patients treated between 2003 and June 2008 were eligible for evaluation if radiological follow-up had been performed at our center for at least 2 years, and there was no definite evidence of local recurrence. Timing, incidence, morphology, and severity of lung changes were determined.
Results: CT scans from 61 patients (68 lesions) with a median follow-up of 2.5 years were evaluated. Within 6 months, 54% of lesions were associated with additional radiological abnormalities, and this figure reached 99% after 36 months. Most changes were scored as mild to moderate, and although the median time to first observation was 17 weeks, 25% appeared ≥1 year post-SBRT. In 47% of lesions, the morphology or severity of changes continued to evolve more than 2 years posttreatment.
Conclusions: Mild-moderate radiological changes are common after lung SBRT. Some degree of late change is nearly universal, and it often continues to evolve more than 2 years post-SBRT. Clinicians should be aware of these radiological findings, which need to be distinguished from the uncommon cases of local failure post-SBRT.
Stereotactic body radiation therapy (SBRT) is a form of high-precision radiation therapy that is frequently delivered in 3 to 8 fractions over 1 to 3 weeks. There is increasing evidence to support its use in selected patients with early-stage non-small cell lung cancer (NSCLC). Prospective multicenter studies have shown that it can achieve local control rates in excess of 88%,1,2 and a meta-analysis of published studies shows that improved local control rates and survival are achieved with SBRT, when compared with conventionally fractionated radiotherapy delivered in 5 to 7 weeks.3 Population-based analyses have revealed that the percentage of elderly patients with stage I NSCLC who underwent radiotherapy increased after the introduction of SBRT, with a corresponding improvement in their survival.4 SBRT outcomes have also been evaluated in patients with stage I NSCLC who have declined surgery,5 and the body of available evidence has been considered strong enough to support phase III trials comparing surgery versus SBRT for first-line treatment of operable patients.6
Computed tomography (CT) is the primary imaging modality for evaluating response and for detecting changes in pulmonary tissues after lung SBRT (Table 1). We previously reported that acute radiological changes develop in approximately 60% of patients.8 The late fibrotic process after high-dose radiation can be dynamic and continue for many years,9,15,17 which at times makes it difficult to distinguish post-SBRT changes from tumor recurrence.9,18–20 For this reason, we have aimed to better characterize the incidence and morphology of late radiological lung changes after SBRT by evaluating post-SBRT CT studies in patients with a minimum of 2 years radiological follow-up.
PATIENTS AND METHODS
Patients and Treatment
The SBRT program at VU University medical center commenced in 2003 and has included evaluations of survival, local control, toxicity, and quality of life. Patients were eligible for this retrospective study if they fulfilled the following criteria: (i) lung SBRT treatment for a stage I NSCLC between 2003 and June 2008, (ii) regular radiological follow-up performed for at least 2 years at our center (rather than their referring center), and (iii) no definite radiological evidence of local recurrence on the study CT scans.
Patient selection, 4D-imaging protocols, use of a risk-adapted fractionation schemes, and the treatment techniques used have all been reported previously.21,22 Treatment was delivered using 8 to 12 noncoplanar static beams and 6 MV photons to a total dose of 60 Gy, calculated with a pencil beam algorithm and prescribed at the 80% isodose line. Fractionation was dependent on tumor size and its location: 3 fractions of 20 Gy were delivered to T1 tumors surrounded by lung parenchyma; 5 fractions of 12 Gy to T2 tumors and T1 tumors in broad contact with the chest wall; and 8 fractions of 7.5 Gy to centrally located tumors and those close to the brachial plexus. Routine follow-up involved outpatient assessments at 3, 6, and 12 months post-SBRT and thereafter every 6–12 months, with a diagnostic CT scan of the thorax and upper abdomen performed at each visit. Fluorodeoxyglucose positron emission tomography-CT scanning is not performed routinely post-SBRT. When intrathoracic disease recurrence is suspected, patients are discussed in a multidisciplinary tumor board consisting of radiation oncologists, pulmonologists, nuclear medicine physicians, and radiologists, before recommendations are made for a follow-up policy. Whether there is definite local recurrence is often uncertain and a common approach involves repeat CT imaging at a short interval (e.g., after 3 months) together with a fluorodeoxyglucose positron emission tomography-CT scan and invasive diagnostic procedures, if appropriate.
Scoring of Radiological Pneumonitis and Fibrosis
Scoring of radiological changes was performed by three radiation oncologists, who together had treated and followed up more than 500 lung SBRT patients. Scoring was performed in a meeting room with digital images of the baseline and follow-up CT scans projected onto a large screen. Scores were assigned by consensus.
Acute CT changes were defined as those occurring within the first 6 months of treatment, using a scoring system described previously8 (Figure 1A and Table 2). Briefly, the five categories of acute findings defined were diffuse consolidation, patchy consolidation, diffuse ground-glass opacities (GGOs), patchy GGO, or no evidence of increasing density. The term “diffuse” was applied to abnormalities that were at least 5 cm in maximum diameter and which contained more than 50% abnormal lung; otherwise, the term “patchy” was applied.
Late CT changes were defined as occurring 6 months after treatment or later and classified into one of four categories10 (Figure 1B and Table 3): “modified conventional pattern” of fibrosis (characterized by consolidation, volume loss, and bronchiectasis ± GGO), mass-like fibrosis (well-circumscribed focal consolidation limited to the tumor region but which is larger than the original tumor), “scar-like fibrosis” (a linear opacity in the tumor region with associated volume loss), or “no evidence of increasing density” (regressing mass at the location of the treated tumor or only normal lung visible).
In addition, our system specified a subjective overall impression of the severity of radiographic findings as follows: “severe” (much more extensive than would usually be expected with SBRT); “moderate” (changes that are common), “mild”/“minor” (slight changes only), or “none.”8
For patients undergoing treatment of more than one lesion, CT changes associated with each lesion were scored separately. Any scans in patients who were undergoing treatment for acute infections, such as an infection, were not scored.
Associations between baseline factors and severity of CT changes were calculated using Spearman's correlation, and the relationship between early and late severity scores was assessed using McNemar's test. Time to onset of first CT changes was estimated using the Kaplan-Meier method, and Cox regression analysis was used to determine whether baseline factors (age, sex, COPD severity, comorbidity score, smoking status, and tumor location) were related to time to onset of first CT change. All statistical tests were two sided with p < 0.05 indicative of statistical significance, and all statistical analyses were performed using the Statistical Package of Social Sciences (SPSS version 15.0, Chicago, IL).
Between 2003 and June 2008, a total of 387 patients underwent SBRT for stage I NSCLC. Out of these, we identified 147 patients who survived more than 2 years post-SBRT and who did not develop local recurrence. Sixty-one patients (Table 4) met all the inclusion criteria for this evaluation, with the commonest reason for ineligibility being CT scans performed in other centers and not stored permanently on the VUmc picture archiving and communication system.
The median age was 71 years, and the median duration of CT follow-up was 2.5 years (range: 2–6.7 years). Thirty-four patients had COPD that was scored as moderate (GOLD III) or severe (GOLD IV), as per the GOLD criteria.23 The median Charlson comorbidity score (nonage adjusted) was 4 (range 2–9), and 49 patients (80%) were medically inoperable. The 61 patients were treated for a total of 68 lesions: six patients were treated for two synchronous lesions, and one patient was treated 2 years after the original course of SBRT for a second primary tumor in a different lung region and was followed up for a further 4 years. The pathological confirmation rate was 34%, consistent with our previously reported experience.21 A total of 325 CT scans were reviewed (median, 5 per patient, range 3–10), on which a total of 364 lesion scores were assigned.
CT scans within 6 months of treatment were available for 67 lesions (assessed in 70 scans). In 46% of cases, there was no evidence of increasing density. In 36 (54%), there were acute parenchymal changes. Acute patterns of CT changes were as follows: 46% of lesions showed no evidence of increasing density, 24% patchy consolidation, 16% diffuse consolidation, 7% diffuse GGO, and 6% patchy GGO.
Late parenchymal CT changes were seen for nearly all lesions (67/68; 99%) at some point during the follow-up period. The incidence of CT changes at 6, 12, 24, and 36 months was 56%, 73%, 87%, and 99%, respectively. A total of 294 late morphology scores were assigned, and the modified conventional pattern of fibrosis was most common (71%), followed by scar-like fibrosis (11%), no evidence of increasing density (11%), and mass-like fibrosis (7%). Most lesions had a maximum severity score of 1 (mild; n = 34; 50%) or 2 (moderate; n = 32; 47%). Only one patient had severe (score = 3) changes after SBRT.
The severity of acute change was predictive of late change severity: 55% of patients with moderate or severe acute changes had moderate or severe late changes. In comparison, only 39% of patients with no/mild acute changes had moderate or severe late changes (p = 0.002). There were no significant correlations between maximum severity score and PTV size (p = 0.14), fraction number (p = 0.95), Charlson score (p = 0.32), smoking status (p = 0.16), laterality (p = 0.51), or severity of COPD as measured by GOLD score (p = 0.93). Time to onset of first CT change was faster in men than in women (median: 26 weeks versus 47 weeks, p = 0.015). Other baseline factors, including age (p = 0.16), smoking status (p = 0.87), PTV size (p = 0.96), laterality (p = 0.64), central location (p = 0.52), COPD severity (p = 0.15), and Charlson score (p = 0.56) were not predictive of time to onset of first CT change.
The cumulative incidence of CT changes is shown in Figure 2. Although the actuarial median time to development of first CT changes was 17 weeks, the first CT change developed more than 1 year after treatment in 25% of lesions. The time course of the morphology and severity of the lung changes is shown in Figure 4. A continual evolution in morphology was commonly observed: many lesions demonstrated a modified conventional pattern after 1 year that evolved thereafter into scar or mass-like patterns (Figure 3A). The severity of CT changes peaked between 1 and 2 years and then plateaued (Figure 3B). Although it appeared to diminish beyond 4 years, this observation is based on a small number of patients. Radiological parenchymal changes continued to evolve long after SBRT, with 32 lesions (47%) showing either a change in morphology or severity of the CT findings more than 2 years after treatment (Figure 4).
To the best of our knowledge, this study reports the longest duration of CT follow-up for assessment of normal tissue changes in patients treated with lung SBRT (Table 1). In addition, it systematically describes the frequency, timing, longitudinal evolution, and severity of post-SBRT lung changes. Although about half of patients developed acute CT changes, we found that late CT changes occurred to some extent in almost all patients. With respect to the timing of these changes, it was noteworthy that in 25% of treated lesions, the first CT changes become apparent more than 1 year after treatment. Importantly, CT changes were often dynamic, with almost half of all cases showing signs of evolution more than 2 years after radiotherapy. Significantly, the proportion of mass-like changes seems to increase in those patients with more than 2 years of imaging follow-up and the severity of changes peaked at 1 to 2 years post-SBRT. Although the severity of early change was predictive of late changes—about half of the patients with moderate-severe acute changes developed late changes of the same severity—additional long-term clinical and radiographic follow-up is still required to better characterize this relationship.24
To put the current data in context, 2 to 6 months after lung SBRT Trovo et al.10 reported a 33% incidence of patchy consolidation/GGO and a 27% incidence of diffuse consolidation, whereas we found 24% patchy and 16% diffuse consolidation at 3 months. From 7 to 12 months and 13 to 18 months post-SBRT, they found 54% and 44% modified conventional pattern, and 20% and 28% mass-like patterns respectively. Whereas, in this study, beyond 6 months post-SBRT, we found a modified conventional pattern in 71% and mass-like fibrosis in 7%. Interobserver variation, sample size, follow-up duration, patient characteristics, and SBRT treatment technique may be among the factors that account for these differences. Similar to Trovo et al.,10 we found no relationship between radiographic changes and the PTV size. However, in contrast with the conclusions of Linda et al.25 in a recent review, we have seen that morphological change is commonplace beyond 2 years after SBRT. The dominant acute (patchy consolidation) and late (solid/discrete consolidation) findings of Aoki et al.16 are consistent with our own observations. Guckenberger et al.9 report similar findings but use the terms dense consolidation, spotted streaky consolidation, and retraction to describe the late changes. Our finding that late consolidation can subsequently evolve into a mass or scar-like pattern is consistent with the report of Takeda et al.17
The fact that multiple series report similar morphologic time trends with conventionally delivered SBRT is perhaps not surprising given that they are all describing pneumonitis and subsequent fibrosis. Nevertheless, the differences in descriptive terminology and scoring metrics highlight that it would be desirable to develop a standardized and validated scoring system that could be consistently applied.24 This is especially important for clinical trials. Although the qualitative method of reporting changes used in this article is currently most relevant to everyday clinical practice, more objective methods for evaluating lung changes post-SBRT are required. A quantitative methodology that uses deformable image registration to correlate lung density changes with radiation dose distributions is currently undergoing evaluation for this purpose.26,27
Although we consider our methodology to be at least as robust as previously reported studies (Table 1), there are some potential limitations. First, it is clear that the follow-up imaging interval will contribute substantially to the estimated timeline for normal tissue responses. In this instance, scans were performed at 3, 6, and 12 months after SBRT, and thereafter every 6–12 months, which means that there could be an uncertainty of up to several months in when normal tissue changes actually occurred. Inevitably, the number of patients at risk declines with time, and so it is feasible that the incidence and the characteristics of morphological change could also alter with longer follow-up and a larger number of patient observations, especially at later time points. For example, observations in this study beyond 2.5 to 3 years are based on a relatively small number of patients. The frequency of changes could be further influenced by the test-retest variability of the scoring systems, which was not specifically evaluated in this report. Although somewhat subjective, the scoring system's descriptive qualities do mean that it could be used in the clinical setting, and the addition of a severity score provides an extra dimension and discriminator over previous reports.
Our report was not intended to focus on the relationship of radiological changes to potential patho-etiological factors, symptoms, or medication. Nor has it considered possible dosimetric risk factors for clinical lung toxicity after SBRT or the effect on lung function.28 In addition, this study does not focus on the identification of local recurrence. It is also important to note that the findings in this study relate to patients treated with multiple noncoplanar conformal beams and 6 MV photons. Volumetric modulated arc therapy is now the standard technique for lung SBRT at our center,29 and changes in the pattern of late radiological changes cannot be ruled out as larger volumes of lung tissue may be exposed to lower doses of radiation in these patients. Finally, it follows that distinguishing lung changes from local recurrence is of great importance, not least of all because there are salvage options for selected patients.30,31 Importantly, in two recent articles describing salvage surgery, the authors reported that the local recurrences were associated with rapid enlargement within a relatively short period after SBRT. Continued radiological follow-up of parenchymal lung change is, therefore, necessary, with multidisciplinary review, increased imaging frequency, metabolic studies, and invasive evaluation as appropriate.
In conclusion, with increasing numbers of patients receiving lung SBRT, it is important that their medical team is aware of specific characteristics of this treatment. This preliminary study of post-SBRT fibrotic changes has demonstrated that long-term CT changes and continued radiographic evolution are common more than 2 years after SBRT. Additional work is now needed to improve the early detection of local progression and to better understand the pathogenesis of lung changes post-SBRT and their long-term physiological and functional effects.
David Palma, MD, was supported by a Canadian Association of Radiation Oncologists/Elekta Research Fellowship.
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