We found that SABR to a dose of 50 Gy delivered in 4 fractions (BED 112.5 Gy) produced a 2-year local control rate of 98.5%, a median OS time of 60 months, and minimal toxicity (minimal grade 3 and no grade 4 or 5). SUVmax on the staging PET/CT scan was the only predictor of OS, with SUVmax less than the median 6.2 being associated with better survival. The MLD to the ipsilateral lung (i.e., the lung containing the lesion to be treated, minus the GTV) was the only significant predictor of grade 2 or 3 RP. Among 130 patients, only two (<2%) experienced LF, one of which occurred simultaneously with DM. The thoracic lymph node recurrence rate of 8.5% was consistent with most reported findings [3–11], and DM remained the dominant pattern of failure. This finding, common in other studies as well [3–7, 9], underscores the need for novel systemic treatments to reduce the incidence of distant failure. Molecular markers may also be helpful for identifying patients who may benefit from adjuvant chemotherapy.
Having other predictive tools in addition to traditional factors such as age, disease stage, performance status, tumor histology, and comorbidities to predict outcome before therapy is begun would be valuable both for the choice of initial treatment and for identifying which patients might benefit from additional systemic therapy. Several surgical series [22–25] showed that pretreatment SUVmax had predictive value in stage I NSCLC treated surgically; one of these studies, an analysis of 136 patients, found that a pretreatment SUVmax >5.5 predicted worse recurrence and survival . However, information on SUV and SABR remains very limited at this time [14–16, 26]. Hoopes et al.  retrospectively evaluated the predictive value of PET SUVmax in a prospective phase I/II dose escalation clinical trial in which SABR was given to 58 patients at doses of 24 to 72 Gy in 3 fractions. Local control rates in that trial ranged from <70% to >95% for the various dose groups, and pretreatment PET SUVmax was not found to predict local control or survival. Another retrospective study by Burdick and colleagues  showed that pretreatment SUVmax did not predict regional failure, distant failure, or survival; however, the 72 patients in that study had also been treated with a wide range of radiation doses (60 Gy in 3 fractions, 50 Gy in 5 fractions, or 50 Gy in 10 fractions), and only 68.1% of patients had had biopsy-proven NSCLC.
The relative strengths of our study were our relatively large population (n = 130) and our inclusion of only patients with biopsy-proven, PET/CT-determined stage I (T1N0M0, T <5 cm) NSCLC who had all been treated with the same dose and who all underwent PET/CT both before and after treatment at the same institution. Our multivariate analyses indicated that having a staging PET SUVmax level >6.2 predicted worse OS, and patients with this feature may benefit from systemic therapy to reduce the likelihood of distant failure, which still remains problematic. The predictive value of PET SUV may well depend on the dose regimen used and perhaps some patient characteristics that we did not consider. Additional studies are needed to validate our observations.
As we and others reported before, PET SUVs measured after SABR may be useful for detecting recurrence (19, 26). In the current study, the staging PET SUVmax levels for the 2 patients who developed local recurrence were 1.8 and 6.5 but had increased to 9.8 and 7.2, respectively, by 1 year after SABR. However, among the other 128 patients who did not experience local recurrence in this study, 32 patients had a SUVmax >3 and 8 patients had a SUVmax >5 within 6 months after SABR. Thus it seems likely that PET images obtained within 6 months after SABR may have a high false-positive rate. Indeed, we and others have noted that PET images with SUV >5 more than 6–12 months after SABR could indicate possible local recurrence, but biopsy is still recommended for confirmation [−25, 26], particularly when salvage surgery is planned .
The most common side effect of SABR in our study was chest-wall pain (12 patients, or 9.3%). A previous study from our group showed that limiting the chest-wall V30 to < 30 cm3 reduced the incidence of chest-wall pain to 5% . However, for lesions next to the chest wall, we recommend that >95% of the GTV plus a 5-mm margin receive at least the full prescribed dose, even if the chest-wall dose exceeds 35 Gy to 30 cm3. In our practice, 35 Gy to 50 cm3 is allowed for lesions close to the chest wall.
RP can be a severe or even fatal side effect of irradiation for lesions within 2 cm of the bronchial tree treated with 54 Gy delivered in 3 fractions . Reports of dose-volume analyses in SABR-induced RP have been limited [13, 17, 18, 28–30]. Barriger and others reported correlations between total lung MLD (<4 Gy vs. >4 Gy), lung V20 (<4% vs. >4%) and grade 2–4 RP among patients treated with SABR to total doses of 42–60 Gy given in 8- to 20-Gy fractions . Matsuo found the association between V25 and symptomatic RP after SABR (17) . With our dose regimen (50 Gy in 4 fractions), our normal-tissue dose-volume constraints (Table 1), and our use of 4D CT-based treatment planning and volumetric on-board image-guided SABR delivery, we did not observe any grade 4–5 RP. We saw no difference in RP between central versus peripheral lesions when normal tissue dose volume constraints were respected and inappropriate cases were excluded, and only 3 patients (2.3%) experienced grade 3 RP. Interestingly, only MLD to the ipsilateral lung was significantly associated with RP in multivariate analysis; among the 65 patients with an ipsilateral MLD ≥9.14 Gy, 14 had grade 2–3 RP (21.5%), whereas among the 65 with an ipsilateral MLD <9.14 Gy, only 1 (1.5%) had grade 2–3 RP (P < 0.001). This finding is consistent with those of Guckenberger and colleagues, who also reported a correlation between irradiated ipsilateral lung volume and SABR-induced RP . In addition, ipsilateral V40 appears to be correlated with grade 2–3 RP when the onset times of RP were considered. The specific dose cutoffs may be different using different dose regimens. Our cutoffs should be considered only when the same or similar SABR dose regimens are used. To minimize the MLD to the ipsilateral lung, one should consider using optimal image guidance to reduce the set-up margin; prescribing the dose to the lower isodose line rather than the higher one; and not using an additional margin between the PTV to the block edge.