To our knowledge, this is the first report to show an association between PET SUVmax
and LR after SBRT for NSCLC. We found that having an SUVmax
greater than 5 at 6 or more months after SBRT was associated with LR after SBRT for Stage I disease or isolated recurrent parenchymal NSCLC. A limited number of studies have used PET to evaluate response after SBRT. A pilot study by Henderson et al.
) reported low-grade activity in the treated lung that persisted for up to 1 year after SBRT. In that study serial PET/CT images were obtained from 14 patients given SBRT to 60 to 66 Gy in 3 fractions (without heterogeneity correction). Patients with high pretreatment SUVs were more likely to have SUV decline than were patients with low pretreatment SUVs. However, this study had small numbers of patients, relatively short follow-up, and no local failure events, which limit or preclude the ability to assess the significance of residual PET activity with regard to LR. In contrast, our study included 128 patients (140 lesions) and 9 LRs (7 proven by biopsy) and had a median follow-up of 31 months. The local control rate after SBRT was lower in the patients treated for recurrent disease than in the Stage I group (3-year actuarial rate of 85.8% vs. 98.5%). In all 8 of the LRs after SBRT for recurrent NSCLC, the primary tumors had been treated with surgical resection and not radiation. It is possible that recurrent disease may have aggressive genomic phenotypes that result in radiation resistance. Of the 10 patients in the recurrent group whose primary tumors (before SBRT) had been treated with radiotherapy, 7 lesions had recurred close to or within the prior radiation field. Interestingly, although those lesions seemed to have higher SUV background (perhaps because of the prior radiation), none of those 7 lesions recurred after SBRT, as confirmed by serial CT, PET/CT, and biopsy.
In cases of LR after SBRT, the SUVmax was significantly higher on PET scans obtained more than 6 months—but not less than 6 months—after SBRT. This finding suggests that PET scans would be most helpful for identifying LR if they are obtained no sooner than 6 months after SBRT; indeed, an SUVmax greater than 5 on scans obtained more than 6 months after SBRT should raise suspicion of LR. We did find some residual PET activity on scans taken more than 6 months after SBRT for some lesions that did not recur. Therefore PET scanning should not be used as the only tool to evaluate LR; biopsy should be considered if salvage chemotherapy, radiotherapy, or surgery would be used in the event of an LR. Although biopsy was strongly recommended to confirm LR in this study, only 7 of the 9 lesions that recurred after SBRT were confirmed by biopsy. However, all lesions were followed by serial imaging, and only those lesions that showed progressive increases in size and SUV were considered to be LRs. Lesions that initially showed avidity after SBRT but subsequently showed declines in size and SUV were considered to reflect consolidative changes, not recurrence. This approach has been used in Radiation Therapy Oncology Group trials, because not all LRs will be biopsied, particularly for patients in poor general condition, with tumors in difficult locations, or with concurrent DM.
Because some post-SBRT lesions did show residual PET activity, the conventional SUV cutoff point of 2.5 to 3.5 may not be appropriate. If a cutoff point of 5 were used instead, the positive predictive value of PET at 6.1 to 12 months after SBRT in our study was 50% and the negative predictive value was 100%. Thus, having an SUV lower than 5 would be reassuring in terms of low risk of LR, and having an SUVmax
greater than 5 after SBRT should prompt a biopsy to rule out LR. Our findings, like those in the study by Henderson et al.
), indicate that pretreatment SUV did not predict LR after treatment of Stage I disease or recurrent disease. The cumulative regional nodal recurrence rate was low (9%) in the Stage I group, and the isolated nodal recurrence rate was 6%. All isolated nodal recurrences were detected by PET, and most were salvaged with systemic and local treatment, indicating that PET has another important role during follow-up.
No consensus has been reached as to the optimal timing of PET after SBRT (12
), but our findings suggest that this timing is crucial. Six patients in our study had LR but could not be distinguished from patients without LR based on PET scans obtained within the first 6 months after SBRT. However, a difference became evident on scans obtained after that time, extending up to 48 months after SBRT. It is possible that PET activity within the first 6 months after therapy reflects an inflammatory response, residual metabolic activity of dying cancer cells, or both and that that activity resolves over time. Therefore we recommend that post-treatment PET scans be obtained no sooner than 6 months after SBRT to evaluate treatment response.
Traditionally, CT has served as the basis for treatment planning and response assessment; however, this technology is limited in its ability to identify small tumor deposits or tumor extension and to distinguish scar tissue or radiation necrosis from malignancy. SBRT in particular can lead to solid consolidations of lung parenchyma, inside or outside target volumes, that can be mistaken for residual or recurrent tumor on CT scans. However, in our cases PET showed no increased activity, and further follow-up including biopsy ruled out recurrence, suggesting—as have Mac Manus et al.
)—that PET is a better predictor of treatment response after radiotherapy than CT. The large radiation fractions used in SBRT may produce segmental atelectasis or focal fibrosis that would result in the appearance of post-SBRT consolidations on imaging and be interpreted as possible LR on diagnostic radiology. Other investigators have found that SBRT produces radiographic changes that can confound CT-based evaluations of treatment response in 60% to 100% of cases (9
). The ability of PET to distinguish malignancy from atelectatic or normal tissue would improve the accuracy of the treatment response assessment and avoid unnecessary biopsy and attendant patient anxiety.
In summary, we found that SBRT produced 3-year actuarial local control rates of 98.5% in the Stage I NSCLC group and 85.8% in the recurrent group. SUVs on PET scans obtained more than 6 months after SBRT are associated with LR in NSCLC. High SUVs (>5) more than 6 months after SBRT should raise suspicion of LR; however, because false-positive findings on PET are possible, biopsy in such cases is still recommended to confirm the recurrence if that would change the management strategy. We further found that SBRT can produce consolidative changes that mimic LR on CT scans. PET scans can be helpful to distinguish such SBRT-induced consolidation from LR and avoid unnecessary biopsy.