Stereotactic body radiotherapy is a preferred strategy for treating medically inoperable patients with stage I NSCLC. For patients with a high operative risk, sublobar resection, rather than lobectomy, is more commonly used resection, and as a potential alternative to surgery, SBRT is encouraged to be discussed within the multidisciplinary cancer care team [35]. To date, no phase III randomized controlled trials comparing SBRT to sublobar resection in high-risk operable patients have been completed. Patients treated with SBRT were those who are medically inoperable as well as potentially operable. A retrospective direct comparison of outcomes between SBRT and sublobar resection is problematic due to the heterogeneous population [36]. Furthermore, defining operative risk is complicated and subjective, especially for patients with a combination of multiple comorbidities, impaired cardiopulmonary function and advanced age. The assessment of operative risk is recommended to be discussed within a multidisciplinary team and may not meet a strict high-risk and inoperable criteria that have been reported in prospective clinical trials (ACOSOG Z4032 and RTOG 0236) [24, 37]. Propensity score matching, which compared outcomes of SBRT and compromised SLR in high-risk operable patients with stage I NSCLC, was used to produce more comparable groups in the current retrospective study.
Previous retrospective studies also attempted to use propensity score matching to balance selection bias of population in comparing survival of SBRT and SLR. Studies were conducted based on institution case series or administrative data from large databases including the Surveillance, Epidemiology, and End Results (SEER) database and the National Cancer Database (NCDB). Port et al [38] reviewed 164 patients who underwent wedge resection or SBRT with clinical stage IA NSCLC and 99 patients were matched by age, sex, and histology, and no significant difference was identified in OS between the wedge resection and SBRT groups (3-year OS 87% vs. 75%, respectively; P = 0.357). Matsuo et al. [39] performed a survival comparison between SBRT and SLR in patients who had stage I NSCLC and were at high risk for lobectomy, and 115 SBRT and 65 SLR patients were enrolled, and the results found that the 5-year OS of SBRT was shorter than SLR before PSM (40.3% and 60.5%, respectively; P = 0.008), and that the Cause-specific death at 5-years was not significantly different. After PSM, 53 patients were matched from each treatment group in terms of age, gender, performance status, tumour diameter, FEV1 and CCI. The differences in 5-years OS (40.4% and 55.6%, respectively, P = 0.124) and cause-specific death (35.3% and 30.3%, respectively; P = 0.427) were insignificant. Shirvani et al. [11] used the SEER database to compare survival outcomes between SLR and SBRT patients age above 66 with stage I NSCLC. In his study, lung cancer-specific survival (LCSS) were not significantly different between the matched SLR and SBRT groups (OS HR 0.82, 95%CI, 0.53–1.27, P = 0.38; LCSS HR 2.14, 95%CI, 0.87–5.26, P = 0.10). Ezer et al. [40] also performed retrospective analysis using the SEER database. Patients aged above 65 years old with stage I–II NSCLC and negative lymph nodes treated with SBRT or SLT were identified. The study showed no differences in OS (HR; 1.20, 95% CI: 0.98–1.49) and cancer-specific survival (HR: 1.48, 95% CI: 0.97–2.42) between two groups after PSM. Our results were consistent with the conclusions from the previous reports, as SBRT achieved comparable survival outcome, compared with SLR after PSM. Thus, our data supported the fact that SBRT could be used as an alternative treatment to SLR.
However, 2 additional population-based analyses were inconsistent with our findings. Paul, et al. [41] compared the survival outcome between thoracoscopic SLR and SBRT using SEER database, and patients aged above 66 with stage I (tumor size ≤ 2 cm) NSCLC were identified. The study found no significant difference in CSS (HR 1.32, 95%CI 0.77 to 2.26; P = 0.32) between two propensity matched groups, however, SLR had a significant advantage in OS, compared with SBRT (HR 1.80, 95%CI 1.33 to 2.43; P < 0.001). Furthermore, Yerokun et al. [42] used the National Cancer Database to compare outcomes between wedge resection and SBRT patients with stage clinical-T1N0M0 (tumors ≤ 2 cm) NSCLC, and SBRT was found to be associated with significantly reduced 5-year survival, compared with wedge resection in both unmatched analysis (30.9% vs 55.2%, P < 0.001) and after PSM analysis (31.0%vs 49.9%, P < 0.001). Therefore, using SBRT as an alternative treatment option to SLR for treating high-risk operable patients for lobectomy is still controversial, thus, prospective study is required to be performed to determine survival rate in SBRT and sublobar resection.
Both SBRT and SLR have inherent disadvantages over lobectomy in terms of disease control. SBRT delivers a very precise and high dose of radiation to a lung tumor in a small number of fractions and achieves more than 90% of local control rate with prescribed dose of BED ≥ 100 Gy [23, 25, 30], however, tumor is still not removed. Low prescription dose of BED and insufficient dose coverage due to the uncertainty of internal tumor movement and/or patient set-up result in worse local control [43–45]. SLR also increases inadequate or positive surgical margins and significantly increases the possibility of local recurrence, compared with lobectomy [7, 22]. Furthermore, both SBRT and SLR do not remove unsuspected intralobar tumor spread. It is still not clear whether SBRT or SLR has a better performance in disease control. Matsuo et al[39] reported a higher local recurrence after SBRT, compared with SLR (28.3% and 14.1% at 5 years, P = 0.059). Port et al. [38] showed that overall recurrence (local and distant) was significantly higher after SBRT (30% VS. 9%, P = 0.016), however, SBRT group had a higher rate of prior lobar resection, which could predispose patients to clinical understaging if some patients had metastatic tumors rather than the second primary tumors. In our study, there were no significant difference in local, regional and distance control between two matched groups, supporting that SBRT could be used as an alternative treatment to SLR.
The type and severity of complications observed after treatments in potentially operable patients differed between SBRT and SLR groups. Adverse events were mostly respiratory injury in SBRT patients and more frequent and severe cardiovascular with SLR. SBRT-related toxicity was mild and similar to previous reports in potentially operable patients, as grades 2 and ≥ 3 radiation pneumonitis occurred in 13.6% and 1.1–2% of patients [30, 31], rib fractures were seen in approximately 3–4.6% patients [31, 32] and grade 3 dermatitis were observed in 3.4% patients [32]. Adverse events might be more frequent and severe in medically inoperable patients with higher prescription dose in fewer fractions (54 Gy in 3 fractions) [24]. Perioperative mortality and morbidity in high-risk operable patients with NSCLC treated with SLR were moderate and similar to a randomized clinical trial(Z4032), in which 9 patients (12%) reported 11 grade 3 respiratory adverse events. Perioperative mortality occurred in 1.4% of the patients [37]. In a study using the SEER-Medicare, unadjusted mortality of sublobar resection at 30-days and 90-days was 1.2% and 4.1%, respectively [11]. There was one treatment-related death after SLR in present work, and SBRT was found to decrease treatment-related toxicities, compared with SLR.
The strengths of present study include that the differences in matching variables were well balanced. Prior lobar resection and CCI, which were not matched, were also no significantly different. Furthermore, survival and disease control after SBRT in our study were consistent with the previous studies, as SBRT achieved high local control rates ranging from 85–96% and 3-years overall survival was 76–95% for patients with potentially operable early-stage NSCLC [28–32, 46]. Our outcomes after sublobar resection were similar to a phase III randomized trial (ACOSOG Z4032) for high-risk operable NSCLC [41].
Several limitations of the present study have to be acknowledged, for example, treatment decision of NSCLC patients relied on proper staging. Sublobar resection is preferred over SBRT to determine nodal status [8]. Potential patients in a disease stage more advanced than stage I, who were associated with poorer prognosis [47], were excluded after SLR, therefore outcomes might be in favor of SLR. As patient selection was conducted by routine examination of PET/CT and appropriate use of invasive staging of mediastinal and hilar nodes with mediastinoscopy or endobronchial ultrasound (EBUS) in high-risk subpopulations with nodal metastases, it achieved higher accuracy and specificity in nodal staging [48–50]. Selection bias in treatment decision-making is unavoidable due to the different characteristics of each treatment modality and the retrospective nature. PSM was applied to reduce differences of patients between SBRT and SLR groups, however, the differences could not be eliminated completely in a single institutional retrospective study. The limited variables of propensity score matching and numbers of patients were less than those analyses, which were based on population-based database. Thus, prospective randomized trials are still required to be performed in the future.