Response assessment and surveillance following stereotactic ablative radiotherapy for lung cancer

Introduction

Surveillance after stereotactic ablative radiotherapy (SABR) is essential for the assessment of primary tumor response, the early detection of locoregional and distant recurrences, and the diagnosis of second primary lung cancer (SPLC). Radiologically, distinguishing local recurrence from radiation-induced changes is challenging as intra-lesional and peri-tumoral parenchymal injury can frequently mimic tumor progression. A proper understanding of the normal tissue changes expected on surveillance imaging after SABR is critical to avoid unnecessary investigations and facilitate timely diagnosis of recurrence. This is particularly important in the context of the expanding role of SABR in fitter patients that could be eligible to aggressive salvage (1), the growing role of SABR in the era of lung cancer screening programs leading to detection of early stage disease (2), and the favourable outcomes shown with various salvage strategies, including surgery, re-irradiation or systemic therapies (3-7). In this review, we will discuss the normal radiological changes expected after SABR, the current and evolving strategies to distinguish recurrence from lung parenchymal injury, as well as the general consensus for surveillance schedule in patients with early-stage non-small cell lung cancer (ES-NSCLC) treated with SABR.

Pattern of recurrence after SABR

The delivery of targeted, hypofractionated radiotherapy for ablation of early-stage lung cancer provides excellent biological efficacy, with 5-year local control around 90% (6,8-10). Across studies, rates of local failure have varied between 7–20%, based on whether local recurrence was defined as progression within or adjacent to the treated volume (6) or progression within the involved lobe (10), and whether pathological confirmation was obtained. Local recurrence can be further classified as in-field (within the target volume), marginal (around the target volume) or within the involved lung lobe (10). As outlined in Table 1, several factors have been associated with local recurrence and recognition of these factors can provide insight for better interpretation of radiological changes and optimization of surveillance strategies. Tumor factors include higher T-stage and tumor size (10), squamous histologic subtype (16,24,25) and high pre-treatment standardized uptake value (SUV) on positron-emission tomography (PET) (19). Treatment factors comprise lower biologically effective dose, planning target volume dose, fractionation and possibly differences in delivery techniques (23,24,26). Despite high local control rates, regional and distant failures are common, with rates of 13% and 20% at 5-year, respectively (9). While the vast majority of recurrences are diagnosed within the first 2 years after SABR, late recurrences can occur up to 5 years post-treatment (6,9,27). In addition, the cumulative rate of SPLC at 5-year post-SABR is 18% (6,10,11); many of these SPLC can be addressed with further ablative treatment when caught early on surveillance imaging.

Lung injury after SABR

The term radiation induced lung injury involves a spectrum of post-treatment parenchymal changes, from radiation pneumonitis (RP) occurring within 6 months of SABR to radiation fibrosis occurring after 6 months (28). The median time to appearance of radiological lung injury is 17 weeks; however, up to 1 in 4 patients will show the first signs of injury as late as 1 year post-treatment (29). RP can be subclinical and diagnosed radiologically, but can also lead to life-threatening clinical RP (30). As many patients with lung cancer suffer from underlying lung disease associated with tobacco smoking, diagnosis of clinical RP is often challenging due to confounding differential diagnosis such as chronic obstructive lung disease exacerbation, interstitial lung disease exacerbation, disease progression or pneumonia (31,32). Clinical RP is characterized by dyspnea, cough, low-grade fever that may require steroid treatment, hospitalisation and in rare instances, respiratory failure that could lead to death (30). A recent pooled analysis from 88 studies showed that clinical RP after SABR is rare, with 9% rate of symptomatic RP (grade ≥2) and less than 2% rate of severe RP requiring oxygen therapy (grade ≥3) (33). However, emerging data suggest that certain subgroups may be at higher risk of developing severe clinical RP post-SABR, including patients with large tumors beyond 5 cm (34,35) and patients with underlying interstitial lung disease (36). On the other hand, in a study analyzing acute radiological injury post-SABR, 54% of patients showed signs of radiological RP on computed tomography (CT) imaging following treatment (37). Table 2 summarizes the main tumor and dosimetric factors that have been associated with radiation-induced lung injury in the literature (33-35,38,43,44). Acute radiological lung injury after SABR is described based on an adapted scoring system previously established for conventional radiotherapy including diffuse (more than 5 cm) and patchy (less than 5 cm) consolidation, diffuse and patchy ground glass opacities or no evidence of increased density (37). Patchy consolidation (24%) and diffuse consolidation (16%) form the most commonly observed parenchymal changes.

Late fibrotic changes occur in most patients and typically appear as an area of increased density in the high-dose region, therefore often conforming to the shape of the initial tumor (28,29). At the histological level, fibrosis is characterized by proliferation of atypical pneumocytes, interstitial elastofibrosis and vascular thickening (45). When present on CT, fibrosis can be classified into three categories: modified conventional pattern (involving consolidation, volume loss, and bronchiectasis), scar-like (linear opacity within the tumor vicinity and volume loss) and mass-like (well-circumscribed focal consolidation surrounding the tumor region) (29,46,47). In a previous study looking at late post-SABR changes, the modified conventional, scar-like and mass-like patterns of fibrosis occurred in 71%, 11% and 7% of patients respectively, while the remaining patients showed no evidence of increasing density. Fibrotic changes have been shown to persist and even sometimes continue to evolve beyond 2 years post-SABR (29). The pattern and severity of fibrosis have been shown to vary based on factors such as dose and fractionation, treatment technique and tumor volume (37,48). Among the radiological patterns of late radiation induced changes, perhaps the most challenging is the mass-like fibrosis, which can frequently be confounded with tumor progression (29,49,50). As opposed to local recurrence, mass-like fibrosis frequently remains stable over time, but progression of the fibrotic pattern over time can be observed, further complicating distinction from tumor recurrence (29).

Strategies for distinguishing lung injury from recurrence

In view of their similar morphology and temporal course, radiation-induced changes and local recurrence can be difficult to differentiate (Figures 1,2) (28,51,52). Failure of timely detection of local recurrence could potentially jeopardize a chance of cure from salvage treatment. Although generally limited to small series and highly selected patients, salvage post-SABR has shown encouraging outcomes with 5-year overall survival reaching 80% (53,54). On the other hand, as reported in several case series of patients who underwent salvage resection and were found to have benign fibrosis (50,55,56), misclassification of radiation induced injury as local recurrence can lead to futile investigations with unnecessary risks and costs. The Response Evaluation Criteria for in Solid Tumors (RECIST) version 1.1, which relies on tumor dimensions assessed on anatomical imaging, remains the most commonly used system for tumor response assessment (57). However, given the expected radiological changes post-treatment, there is general agreement that these criteria are not well suited for response assessment post-SABR. In fact, the poor performance of tumor dimension changes as a predictor of local recurrence within 6 months of SABR was previously shown (58-60). Currently, a diagnosis of local recurrence post-lung SABR is generally based on radiological findings on serial CT, in combination with hypermetabolism on 18-fluoro-2-deoxy-D-glucose (FDG)-PET and pathological confirmation whenever possible.

Figure 1 Serial CT scans and FDG-PET/CT from a patient with fibrotic radiation-induced changes. An 81-year-old man treated with robotic SABR for a T2bN0 adenocarcinoma of the right upper lobe to a dose of 60 Gy in 5 fractions; the patient developed late radiation fibrosis. SUV_max from FDG-PET at 4 years post-SABR was 0.6. Sequential imaging shows progressive installation of ground glass opacities and consolidation: (A) planning CT; (B) CT at 3 months; (C) CT at 4 years; (D) FDG-PET/CT at 4 years. Red and green contours represent respectively the gross tumor volume and planning target volume on the planning CT image. CT, computed tomography; FDG-PET, 18-fluoro-2-deoxy-glucose positron-emission tomography; SABR, stereotactic ablative radiotherapy; SUV, standardized uptake value; SUV_max, maximum SUV.

Figure 2 Serial CT scans and FDG-PET/CT from a patient with pathologically proven local recurrence. A 68-year-old woman treated with robotic SABR for a T1aN0 adenocarcinoma of the right upper lobe to a dose of 60 Gy in 3 fractions. She developed biopsy-proven local recurrence 3 years post treatment, with SUV_max of 4.2 on FDG-PET. Sequential imaging shows installation of a mass-like consolidation: (A) planning CT; (B) CT at 6 months; (C) CT at 3 years; (D) FDG-PET/CT at 3 years. Red and green contours represent respectively the gross tumor volume and planning target volume on the planning CT image. Several high-risk CT features can be seen, notably sequential enlargement, enlarging opacity after 12 months, craniocaudal growth and bulging margin. CT, computed tomography; FDG-PET, 18-fluoro-2-deoxy-glucose positron-emission tomography; SABR, stereotactic ablative radiotherapy; SUV, standardized uptake value; SUV_max, maximum SUV.

Several high-risk CT features predictive of local recurrence were previously identified in a systemic review by Huang et al. (28); these features included: (I) enlarging opacity at the tumor site, (II) serially enlarging opacity, (III) loss of linear margin, (IV) convex bulging margin, (V) loss of air bronchograms, and (VI) enlarging opacity after 12 months (28). These criteria, along with the additional feature of craniocaudal growth ≥5 mm or ≥20%, were later validated in a matched cohort of 36 patients, including 12 patients with pathological proof of recurrence (61). In the latter study, an enlarging opacity after 12 months and craniocaudal growth were found to be the best predictors of recurrence. Furthermore, the presence of ≥3 high-risk CT features was found to have a sensitivity and specificity for local recurrence beyond 90%. These high-risk CT features were independently validated in another cohort of biopsy-proven cases of recurrence, which found this time that bulging margin, loss of linear margin and craniocaudal growth were the strongest features associated with local recurrence (62).

There remains controversy around the diagnostic performance of these high-risk CT features, as findings across studies have not been unanimous. In fact, in a recent study from Ronden et al. (63), up to half of the patients without locally recurrent disease had developed high-risk features, and the presence of ≥3 high-risk CT features was observed in up to 25% of patients without recurrence. These conflicting findings, along with the inconsistent presence of pathological confirmation of recurrence across studies and the generally small cohorts of patients in studies investigating CT-based radiological changes, constitute limitations. However, a recent expert consensus recommended that until better methods emerge, the following CT features should raise suspicion for local recurrence: infiltration into adjacent structures, bulging margins, sustained growth, loss of air bronchograms, as well as mass-like, spherical and craniocaudal enlargement (64). It was also recommended that the number of features should be used to classify patients as being at low, intermediate, or high-risk of recurrence (64).

Functional imaging

The search for optimal imaging biomarkers for the effective diagnosis of local recurrence is an active area of investigation. In contrast to simple anatomic imaging, the use of functional imaging holds the promise of further characterizing tumors activity and aggressiveness by providing information regarding tumor glucose uptake, perfusion, hypoxia and proliferation.

FDG-PET is a functional imaging that has largely been integrated into routine clinical practice in patients presenting findings suspicious of recurrence on CT imaging. Due to the risk of false-positive uptake from RP, FDG-PET for investigation of local recurrence has increased specificity when obtained >6 months post-SABR (65,66); however, it should be stressed that inflammatory FDG avidity can persist beyond 12 months post-SABR (61). Given the conflicting findings in the literature, the optimal maximum SUV (SUV_max) threshold associated with local recurrence remains uncertain. Several studies support that a post-SABR SUV_max ≥5.0, or greater than the pre-treatment SUV_max, are the most sensitive findings of local recurrence (20,28,67). In a study including 132 patients with ES-NSCLC treated with SABR and followed with serial FDG-PET, SUV_max ≥5.0 after 3–6 months post-treatment had a positive predictive value of recurrence of 83% (68,69). In another study including 17 local recurrences (not all pathologically proven), SUV_max cutoffs of 3.2 and 4.2 on early and delayed acquisitions had a sensitivity and specificity for recurrence of 100% and 96–98%, respectively (66). However, FDG-PET values are subject to significant variation due to lack of protocol standardization across institutions, differences in timing of acquisition and quantity of injected FDG, as well as patient’s related factors such as size or weight (70,71). Hypoxia PET tracers such as ¹⁸F-fluoromisonidazole (F-MISO) have been reported pre-clinically for assessment of response after lung SABR in mice (72) but future studies are needed to define their clinical utility.

Lung magnetic resonance imaging (MRI) has historically been of limited use due to the issues of respiratory motion and low tissue density of the parenchyma, inducing signal-to-noise ratio reduction and magnetic susceptibility effects. In recent years, technology enhancements have allowed faster acquisition times and improved respiratory-gating techniques, which have resulted in better quality of lung MRI (73). The use of functional MRI, including diffusion weighted diffusion-weighted MRI (DW-MRI) to quantify cellular density within the tumoral region (74,75) and dynamic contrast-enhanced (DCE) to measure perfusion (76-78) are promising avenues for response assessment. In one study, DW-MRI was found to be an early predictor of treatment response after lung SABR, with significantly lower apparent diffusion coefficient values at 3 and 6 months in patients eventually developing local recurrence (74). Similarly, preclinical work support that hypofractionated radiotherapy to the lungs induces important vascular damage within the tumor that could be assessed with perfusion imaging such as DCE-MRI (79). Further work will help define the role of functional MRI for surveillance after lung SABR.

Radiomics

Radiomics is an emerging field involving the extraction of quantitative data from imaging using advanced image analysis (80,81). To undertake radiomics analyses, a region of interest is defined, from which a series of radiomic image features can be calculated (82). Such features include first-order statistics based on the distribution of the intensity histogram (mean, median and standard deviation), and second-order features that take into account the neighbouring relationships of voxels within the region of interest. Radiomics-based quantification of lung density for assessment of SABR-induced lung damage has been investigated in several studies (83-85). Based on a dataset of 45 patients, a radiomic signature consisting of five image features could predict recurrence within 6 months post-SABR with a false-positive rate of 24% and a false-negative rate of 23% (60). The latter study showed that computer-aided texture analysis allowed earlier detection of recurrence post-SABR compared to physician-based scoring of high-risk features on CT. Another study by Fave et al. showed promising incorporation of radiomics on CT immediately at the end of treatment, to stratify patients into low vs. high risk of local relapse (86). Although the field of radiomics remains at its early stage, these findings suggest a promising role of texture analysis for early diagnosis and optimal therapeutic decision in patients treated with lung SABR.

Recommended surveillance schedule after lung SABR

Many guidelines, including those from the National Comprehensive Cancer Network (87) and the American Association of Thoracic Surgery (88), recommend follow-up CT examinations every 6 months for at least 2–4 years, followed by annual follow-up CT examinations. In a recent expert consensus from an International Delphi Consensus Study, there was general agreement that patients should be followed with routine CT post-SABR at 3, 6, and 12 months in year 1, every 6 months in year 2 and annually in years 3 through 5, and that an FDG-PET should obtained in case of suspicion of local recurrence (64). Although the exact frequency and duration of follow-up can be left at the discretion of the treating physician, more rigorous follow-up and lower threshold to trigger investigations is justified in patients at higher risk of local recurrence, including those with larger tumors, suboptimal radiation dose, or high pre-treatment SUV_max (12,19,89). Although no definite guidelines exist for follow-up of patients with suspected recurrence, one suggested algorithm proposes that patients at low-risk (with no suspicious CT features) could have routine follow-up, patients at intermediate-risk (with ≤2 suspicious CT features) could benefit from FDG-PET/CT or closer follow-up CT after 3 months, while patients at high-risk (with ≥3 suspicious features on CT) could proceed to a biopsy or salvage therapy after careful evaluation and discussion in a multidisciplinary tumor board (61). A schematic summary of the recommended surveillance after lung SABR is presented in Figure 3.

Figure 3 Schematic summary of the recommended surveillance after lung SABR based on the presence of high-risk CT features suspicious of local recurrence. CT, computed tomography; FDG-PET, 18-fluoro-2-deoxy-glucose positron-emission tomography; SUV, standardized uptake value; SBAR, stereotactic ablative radiotherapy.

Conclusions

Although lung SABR yields excellent tumor control outcomes, local relapse does occur in about 1 in 10 patients and is often difficult to distinguish from radiation induced lung injury such as pneumonitis or late fibrotic changes. Several tumor and treatment related factors are predictive of local control including gross tumor volume, histologic subtype, pre-treatment SUV and biologically effective dose. Surveillance with serial CT acquisition over the 5 years following treatment is recommended in ES-NSCLC patients treated with SABR. Usage of systematic imaging CT features to detect high-risk features of local recurrence such as bulging margins, sustained growth and craniocaudal growth can help identify patients that could benefit from further investigations, including functional FDG-PET imaging, biopsy or even salvage treatment. In the future, quantitative functional imaging and radiomics may help further refine post-SABR tumor response assessment.

Acknowledgments

Funding: None.

Footnote

Conflicts of Interest: H Bahig received a research grant from Varian Medical Systems, unrelated to current work. D Mathieu has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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