Study selection
A total of 5549 records were initially identified through the databases and 28 additional researches through other sources. After exclusion of duplicate studies and irrelevant papers, this systematic review finally included 39 studies (11, 15-52). These contained one pooled analysis of two randomized controlled trials and one pooled analysis of a randomized controlled trial and a prospective study, while the rest of 37 studies were all observational researches included 25 studies with propensity-matched data and one study with matched data. Finally, 28 studies met the selection criteria for quantitative meta-analysis. All studies included in this study at least reached moderate-quality under the assessment of Newcastle-Ottawa Scale reported scores. The select process is depicted in Figure E1 and the detailed characteristics of studies were showed in Table 1.
Patient and tumor characteristics
There are 21 unmatched studies and 19 matched studies included meta-analysis. Basic characteristics of matched and unmatched patients included for meta-analysis is showed in table E1. The commonly propensity-matched factors contained age; sex; performance status (PS); Charlson comorbidity index (CCI); respiratory function; tumor diameter, tumor stage or location, and histology. The mean age for unmatched patients is 62.0-78.3 for those who underwent surgery,71-82.6 for those who underwent SBRT. For matched patients, the mean age is 58.7-78.3 and 60.3-78.2 respectively. The characteristics of patients and tumors in matched surgery cohorts inclined to be older or with poor pulmonary function, CCI, PS or greater clinical tumor diameter. And the histology type for matched and unmatched patients is displayed in table E2, adenocarcinoma and squamous cell carcinoma accounts for the most of NSCLC. For patients who underwent SBRT, 49.2% at most did not get a histopathologic proof of NSCLC(28). The more detailed treatment information is presented in table E3. Most patients who underwent lobectomy received mediastinal lymph node dissection or sampling(15, 31, 41, 45, 47). And for patients who underwent SLR, lymph node dissection was rarely reported. For unmatched patients who underwent surgery, there is up to 24.5% upstaged(41),17.1% received adjuvant chemotherapy(45) and 5.4% received adjuvant radiotherapy(43). For unmatched patients who underwent SBRT, there is up to 12.1% received adjuvant chemotherapy(21). The median follow-up time is 27.5-66 months for unmatched surgery cohorts and 16-69 for months for unmatched SBRT cohorts.
Primary analysis: Results of survival outcomes of surgery versus SBRT
A total of twenty studies reported comparative OS for unmatched patients with early-stage NSCLC who underwent SBRT(N=39604) and surgery(N=179710). The pooled results showed the patients after surgery had a significantly superior OS compared those after SBRT (HR, 0.52;95% CI, 0.45-0.60; P=.0000; I2=96.2%; Figure 1, A). In the matched cohorts, the comparative OS for patients who underwent surgery(N=19056) and SBRT(N=19060) is consistent with the unmatched cohorts (HR, 0.62; 95% CI, 0.53-0.72; P=.0000; I2=86.0%; Figure 1, B). And comparative CSS for both unmatched and matched patients who underwent SBRT or surgery, demonstrated significantly superior outcomes after surgery (Figure E2).
For DFS, RFS or PFS, we included twelve relative studies in our meta-analysis (15, 18, 21, 22, 24, 25, 30, 31, 37, 44, 45, 47). Eight studies defined DFS, RFS or PFS as the time from treatment procedure until tumor recurrence or death(15, 18, 21, 22, 31, 44, 45, 47), showing superior outcomes after surgery (matched studies: HR, 0.60;95% CI, 0.46-0.79; P=0.000; Figure E3, B). Three studies defined RFS or PFS as the time from the first day of diagnosis to the date of tumor recurrence(25, 30, 37), but the pooled outcome of matched studies demonstrated no significantly difference between SBRT and surgery (HR, 0.61;95% CI, 0.34-1.08; P=0.091; Figure E3, B).
All of the pooled results of LRC, DC and RC for unmatched patients demonstrated superior outcome for surgery (Figure E4-6, A). But the LRC, DC and RC for matched patients showed no significantly difference between SBRT and surgery (Figure E4-6, B). However, the pooled results of LC for both unmatched and matched cohorts stand by the surgery (Figure E7).
The 30-day and 90-day mortality for unmatched patients who underwent surgery was respectively 0-3.7 and 0.18-4.0, while for those who underwent SBRT is 0-0.5 and 1.3-1.4 (Table E4).
Secondary analysis: Results of different resection types or surgical approaches versus SBRT
Eight studies reported OS for unmatched patients who underwent lobectomy and SBRT, showing that the patients after surgery had a superior OS compared to those after SBRT (HR, 0.45;95% CI, 0.37-0.55; P=.0000; I2=87.7%; Figure E8, A). In the matched cohorts, the pooled OS is consistent with the unmatched cohorts (HR, 0.55; 95% CI, 0.37-0.82; P=0.003; I2=78.5%; Figure 2).
The HR of OS for unmatched and matched patients who underwent SLR and SBRT is lightly higher than those who underwent lobectomy and SBRT, but still showed that the patients after surgery had a significantly higher OS compared those after SBRT (unmatched cohorts: HR, 0.62;95% CI, 0.56-0.68; P=.0000; I2=83.0%; Figure E8, A. matched cohorts: HR, 0.66;95% CI, 0.61-0.71; P=.0000; =50.7%; Figure 3).
The comparative OS for both matched and unmatched patients who underwent VATS and SBRT demonstrated significantly superior outcome for patients after surgery (Figure 3 and Figure E8 B). In the subgroup of thoracotomy, the HR of comparative OS for two matched studies was slightly higher than the subgroup of VATS, but still stand by the surgery (Figure 3).
Additional analysis and sensitivity analysis
For the matched cohorts in the primary analysis, the HR of OS among patients with unspecific age, ≥65 and ≥75 years old showed a gradually decrease (Figure E9, B). The matched cohorts with unspecific age and ≥65 showed a significantly superior OS compared those after SBRT (HR in the subgroup with unspecific age, 0.58;95% CI, 0.49-0.70; P=.000. HR in the subgroup with ≥65 years old, 0.66;95% CI, 0.45-0.99; P=.045). The only one matched cohort with ≥75 years old included in the meta-analysis demonstrated no significant difference of OS between surgery and SBRT.
There were four studies reported OS of matched operable patients, demonstrated that surgery had same OS with SBRT (HR, 0.71;95% CI, 0.24-2.16; P=0.549; Figure 4), although the unmatched operable cohorts showed a significantly higher OS compared those after SBRT (HR, 0.42;95% CI, 0.24-0.72; P=0.002; Figure E10). For comparative OS, the pooled estimate for histopathologically confirmed NSCLC was higher than the outcome for clinical NSCLC irrespective of matching (Figure E11).
Further, sensitivity analysis showed the effect of individual studies did not act any major effect on the point estimates of OS. Egger s test indicated no obvious publication bias of included studies.