Cons: After lung stereotactic ablative radiotherapy for a peripheral stage I non-small cell lung carcinoma, radiological suspicion of a local recurrence is not sufficient indication to proceed to salvage therapy

Stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy (SABR) has become the standard of care for inoperable stage I non-small cell lung carcinoma (NSCLC). SBRT for peripheral tumors is well tolerated with minimal side effects (1,2) and results in excellent local control (2). While local recurrence is uncommon following lung SBRT, with the increasing use of SBRT in operable patients, there is a greater need to identify and manage local recurrences.

Radiation induced lung injury (RILI) is a common occurrence after SBRT. RILI is a benign process involving fibrocytes and other inflammatory cells (3). It is complex in its appearance, evolves over time (4,5) and its appearance can vary with treatment technique (6). RILI from SBRT is of a different nature than radiographic changes seen from conventional radiotherapy treatments. It is uncommon for patients to develop symptomatic radiation pneumonitis after lung SBRT (1), but radiographic changes of RILI do occur in the majority of patients starting 3-6 months after SBRT and can evolve for years (7). One classification system describes four patterns of RILI, namely the modified conventional, mass-like and scar-like fibrosis as well as the “no evidence of increased density” pattern (5). Mass-like fibrosis, defined as a “well-circumscribed focal consolidation limited to area surrounding the tumor and the abnormality must be larger than the original tumor” (5) is a particularly challenging form of RILI to distinguish from local recurrence (5,8,9) and leads to clinical concerns relating to whether the changes are suspicious and what, if any, interventions are appropriate (9,10). However, the majority of cases of mass-like fibrosis remain stable over time without development of recurrence, and are thus confirmed as RILI.

There is no uniform definition of local control following SBRT, whether in studies or in clinical practice. RECIST criteria, which classify an increase of ≥20% in size as “progressive disease”, has been used in early SBRT studies (RTOG 0236) but are limited by RILI (10). The next generation of studies, such as RTOG 0813 have distinguished between local enlargement and local failure, and have required that an increase in tumor dimension of 20% be confirmed with either FDG-PET imaging with uptake of a similar intensity as the pretreatment staging PET, or a biopsy confirming viable carcinoma, before a local failure is declared (11).

Given the limitations of tumor measurement on CT scans in the post-SBRT setting, efforts were made to identify high risk features, beyond size, that would help identify local failure on CT scans. Kato et al. proposed the following high-risk features on a series of 27 cases (with 5 local recurrences): a bulging margin, disappearance of air bronchograms, appearance of pleural effusion, or increase in the abnormal opacity after 12 months (12). This work was expanded by Huang et al., on a matched-case series of 12 biopsy-proven recurrences; they found the previous criteria valid and added an additional feature cranio-caudal growth (13). Several groups have attempted to validate these high risk radiological features. Halpenny et al. found only new bulging margin as a significant predictor; they had 10 local failures, four of which were biopsy proven (14). Peulen et al. using a multi-institutional series including 53 local recurrences (13 of which were biopsy proven) suggested a simplified model that combined bulging margin and cranio-caudal growth (15). Studies describing and validating these features have a common significant limitation, which is the lack of biopsy confirmation of all cases that were deemed to be “recurrence”. This likely reflects the challenges of considering a biopsy in a predominantly medically inoperable patient population and the ethical considerations of subjecting a patient to a potentially risky procedure if there is not curative salvage therapy that can be offered.

Given the limitations of CT to distinguish RILI from recurrent cancer, several groups have examined FDG-PET as an alternate or complementary approach. One caveat to the interpretation of FDG-PET data is the lack of standard inter-institutional approach to FDG-PET scans, which can impact the measured SUV values. Additional limitations of FDG-PET scans include the hypermetabolic activity seen in RILI (16) and a lack of validated SUV cut-offs for local recurrence. One algorithm proposes SUV_max of ≥5 as a high-risk threshold for local failure (17). A series of 128 patients concluded that SUV_max of ≥5 should prompt a biopsy; however, the positive predictive value was only 50% (18). A series with 6 biopsy proven local recurrences reported high SUV_max, all greater the 5 (19). However, other reports describe cases that exceed that SUV threshold but were proven to be benign changes without any evidence of residual or recurrent tumors (20,21), as illustrated in Figure 1. There are other reports of highly suspicious radiographic findings prompting surgical resection without evidence of disease (8,21), but the true frequency of this phenomenon is unclear. Thus, there is currently no established radiological (CT and/or PET) criteria that has sufficient sensitivity and specificity to confirm local failure. Distinguishing RILI from recurrence ideally requires the use of complementary imaging modality to guide the selection of patients most likely to have a local recurrence, who should proceed to biopsy. However, a biopsy done too early after SBRT may result in a false positive biopsy as the time at which patients will develop maximal pathological response to high-dose per fraction radiation such as SBRT is unknown. There have indeed been reports of false positive biopsy following SBRT at 5 and 14 months (3).

Figure 1 Illustrative case where salvage lobectomy on the basis of high suspicion radiological evidence of local recurrence 7-month post SBRT revealed fibrosis with no evidence of viable cancer. (A) Baseline CT scan image of biopsy proven non-small cell lung cancer, T1N0, that was then treated with SBRT (48Gray in 4 fractions); (B) CT image 3-month post SBRT showing increased consolidation and pleural thickening; (C) CT image 6-month post SBRT, showing increasing mass-like consolidation with craniocaudal growth; (D) FDG-PET scan 7-month post SBRT, SUV_max 8.9 (pre-treatment SUV_max 4.3).

The limitations of CT and FDG-PET scans to diagnose local failure have prompted investigators to explore alternate imaging modalities. One study is using thoracic MRI scans in patients considered to have either stable fibrosis or recurrent cancer; a number of MRI sequences are obtained, that provide anatomic and functional characterization of the area of interest, with the hypothesis that MRI will be able to distinguish fibrosis from tumor recurrence (22). Another study is investigating FLT-PET scans, hypothesizing that the integration of thymidine into DNA as a tool to assess proliferation, can distinguish fibrosis for local recurrence (23). The use of biopsy must be taken in context with a patient’s medical status and the options available for salvage. All such cases should be discussed in a multi-disciplinary setting.

The importance of confirming a local failure using pathology before embarking on salvage interventions is impacted by the potential risk and toxicity associated with those salvage treatments. The two main forms of salvage therapy, salvage surgery and re-irradiation, are both associated with potential toxicities. There is limited experience of salvage surgery in the literature. This likely reflects the patient population who received SBRT, as in general, SBRT is used in medically inoperable or high risk patients for surgery, with only a minority of patients currently being medically operable and choosing to have SBRT instead. Given the challenges of operating once post radiation fibrosis has occurred, and patients’ age and comorbidities, salvage surgery for local failure post SBRT is clearly a high-risk option and should only be contemplated after careful consideration of risks and benefits. Small series looking at salvage lobectomy have reported low rates of morbidities in very well selected patients in centers with high surgical volume and expertise (20,21,24).

Salvage radiation in the form of additional SBRT has also been reported. A report on 29 patients from the Karolinska University Hospital demonstrated this approach can achieve local control, however there is a significant risk of grade 5 toxicity, massive hemoptysis, particularly with more central tumors and larger volumes (25). It is our recommendations that such risks should be considered only for patients with pathologically proven tumor recurrence.

Systemic therapy, including targeted therapy, chemotherapy and immunotherapy may be an option for patients with isolated local failures but is not considered curative, and is associated with side-effects and risks, and there is no evidence currently that early institution of such therapy would clearly improve patient outcomes, particularly as isolated local failure may not be causing any symptoms.

Conclusions

Radiological suspicion of local recurrence following lung SBRT in the absence of pathological proof of recurrences does not have sufficient sensitivity and specificity to select patients to potentially toxic salvage therapies. While proposed models of high-risk CT features may be helpful, no current models have been adequately validated with confirmed local failure; the “gold standard” evidence is scant. In the future, purely imaging based combinations of CT and novel imaging modalities must be validated against biopsy proven failures to identify local recurrences without a biopsy. Until then, patients with high clinical and radiographic suspicion of local recurrence should undergo, where feasible, biopsy confirmation prior to consideration of salvage therapy to maximize cure rates and the therapeutic ratios for patients with early stage lung cancer.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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