Most patients had a pretreatment forced expiratory volume during the first seconds (FEV1) value and DLCO < 60% of predicted (60% and 84% of the patients, respectively). The median tumor diameter was 2 cm. Of the 68.2% of patients who did not have chronic hypoxemic respiratory failure before SABR, 16% developed a new requirement for supplemental oxygen. Sixty-two tumors (89.9%) were peripheral. There were 4 local recurrences (5.7%), 10 regional (different lobe and nodal) failures (14.3%), and 15 distant metastases (21.4%).
Nineteen of 67 patients (26.3%) had acute toxicity of which 9 had acute grade ≥ 2 toxicity; information regarding toxicity was missing on 2 patients. Thirty-two of 65 (49.9%) patients had late toxicity of which 20 (30.8%) had late grade ≥ 2 toxicity. The main factor associated with development of acute toxicity was pretreatment oxygendependence (P = .047). This was not significant when comparing only inoperable patients. Twenty patients (29.9%) developed some type of acute toxicity; pulmonary toxicity was most common (22.4%) (Table 3). All patients with acute toxicity also developed late toxicity except for 1 who died before 3 months. Predominantly, the deaths in our sample were from causes other than the malignancy or treatment, such as sepsis, deconditioning after a fall, cardiovascular complications, etc. Acute toxicity of grade ≥ 2 was significantly associated with late toxicity (P < .001 for both) in both operable and inoperable patients (P < .001).
Development of any acute toxicity grade ≥ 2 was significantly associated with oxygendependence at baseline (P = .003), central location (P < .001), and new oxygen requirement (P = .02). Only central tumor location was found to be significant (P = .001) within the inoperable cohort. There were no significant differences in outcome based on pulmonary function testing (FEV1, forced vital capacity, or DLCO) or the analyzed PFT subgroups (FEV1 < 1.0 L, FEV1 < 1.5 L, FEV1 < 30%, and FEV1 < 35%).
At the time of data collection, 30 patients were deceased (43.5%). There was a statistically significant association between OS and operability (P = .03; Table 4, Figure 1). Decreased OS was significantly associated with acute toxicity (P = .001) and acute toxicity grade ≥ 2 (P = .005; Figures 2 and 3). For the inoperable patients, both acute toxicity (P < .001) and acute toxicity grade ≥ 2 (P = .026) remained significant.
Discussion
SABR is an effective treatment for inoperable early-stage NSCLC, however its therapeutic ratio in a more frail population who cannot withstand biopsy is not well established. Additionally, the prevalence of benign disease in patients with solitary pulmonary nodules can be between 9% and 21%.6 Haidar and colleagues looked at 55 patients who received empiric SABR and found a median OS of 30.2 months with an 8.7% risk of local failure, 13% risk of regional failure with 8.7% acute toxicity, and 13% chronic toxicity.7 Data from Harkenrider and colleagues (n = 34) revealed similar results with a 2-year OS of 85%, local control of 97.1%, and regional control of 80%. The authors noted no grade ≥ 3 acute toxicities and an incidence of grade ≥ 3 late toxicities of 8.8%.1 These findings are concordant with our study results, confirming the safety and efficacy of SABR. Furthermore, a National Cancer Database analysis of observation vs empiric SABR found an OS of 10.1 months and 29 months respectively, with a hazard ratio of 0.64 (P < .001).3 Additionally, Fischer-Valuck and colleagues (n = 88) compared biopsy confirmed vs unbiopsied patients treated with SABR and found no difference in the 3-year local progression-free survival (93.1% vs 94.1%), regional lymph node metastasis and distant metastases free survival (92.5% vs 87.4%), or OS (59.9% vs 58.9%).8 With a median OS of ≤ 1 year for untreated stage I NSCLC,these studies support treating patients with empiric SABR.4
Other researchers have sought parameters to identify patients for whom radiation therapy would be too toxic. Guckenberger and colleagues aimed to establish a lower limit of pretreatment PFT to exclude patients and found only a 7% incidence of grade ≥ 2 adverse effects and toxicity did not increase with lower pulmonary function.9 They concluded that SABR was safe even for patients with poor pulmonary function. Other institutions have confirmed such findings and have been unable to find a cut-off PFT to exclude patients from empiric SABR.10,11 An analysis from the RTOG 0236 trial also noted that poor baseline PFT could not predict pulmonary toxicity or survival. Additionally, the study demonstrated only minimal decreases in patients’ FEV1 (5.8%) and DLCO (6%) at 2 years.12
