DISCUSSION


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As an important adjuvant treatment, the effect of postoperative chemotherapy in NSCLC is an important concern of oncologists. In recent years, several meta-analyses that explored the benefits of postoperative chemotherapy for NSCLC had been published, and the main characteristics are listed in Table 3. They demonstrated that postoperative chemotherapy was beneficial for NSCLC, but they did not discuss the survival benefit of chemotherapy without radiotherapy in early stage patients. Therefore, this meta-analysis was restricted to postoperative chemotherapy alone and early stage NSCLC.

(To view a larger version of Table 3, click here.)

We found survival advantages of receiving postoperative chemotherapy alone in early NSCLC patients. Subgroup analysis showed that this advantage had statistical significance in stages I and IB but not in stage IA. Similar results were also reported in other meta-analyses. Hamada et al38 focused on postoperative chemotherapy with UFT in stage I NSCLC and reported that 5-years OS rate was significantly higher in the chemotherapy group compared to control group (81.5% versus 77.2%, P=0.011, HR: 0.74). Bria et al39 reported that patients with stage I–III disease who received cisplatin-based chemotherapy had a longer survival than those who underwent surgery alone in all stages including early NSCLC. However, the relative risk (instead of the more frequently used HR) and non-full paper trials in Bria’s analysis might influence the accuracy of survival determination. Unlike stages IB and I, we did not observe an OS benefit of chemotherapy for stage IA disease (HR: 0.76, 95% CI, 0.39–1.50). This result was compatible with the Lung Adjuvant Cisplatin Evaluation Collaborative Group,10 which performed a trial on cisplatin-based chemotherapy in patients with stage I–III disease. Negative efficacy of postoperative chemotherapy in stage IA was based on only three trials, likely because stage IA patients are rare at initial surgery and these patients are less likely to receive postoperative chemotherapy. These results need to be confirmed in large RCTs.

Consistent with the study conducted by Berghmans et al40 we found that both cisplatin-based and single UFT chemotherapy significantly improved OS. But their analysis included two trials presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, which might cause the imprecise effect because of insufficient data (ie, randomization procedures, patient allocation, or trials quality). A meta-analysis including stage I–III patients conducted by Hotta et al4 also suggested that both cisplatin-based chemotherapy (HR: 0.89, P=0.012) and single UFT (HR: 0.80, P=0.015) significantly improved OS. This postoperative chemotherapy benefit in OS was also confirmed by Sedrakyan et al.41 These data strengthened our results regarding subgroup analysis of different chemotherapy regimens. Importantly, advantages of cisplatin-based and single UFT chemotherapy identified in our study were superior to those reported in other meta-analyses. It should be noted that the above three meta-analyses did not investigate the effect of postoperative chemotherapy on DFS, while we did it. Our results demonstrated that cisplatin-based chemotherapy significantly improved DFS, but single UFT chemotherapy did not. In addition, we provided the first evidence that cisplatin-based chemotherapy was better than single UFT chemotherapy with regard to DFS for early NSCLC patients by ITC software, but the OS benefits were similar for the two kinds of chemotherapy regimens. However, this finding should be interpreted carefully, because all the UFT trials were conducted in Japan and this agent was not extensively administrated in other areas. In addition, the small number of studies was not sufficient to draw exact conclusions. More RCTs about postoperative UFT chemotherapy for NSCLC outside Japan should be conducted in the future.

The PORT meta-analysis16 indicated that postoperative radiotherapy had a detrimental effect on survival, particularly for early stage NSCLC patients. So, it was unreasonable that postoperative radiotherapy was included in the meta-analysis of postoperative chemotherapy, because it might increase chemotherapy toxicities. However, these meta-analyses listed in Table 3 still permitted postoperative radiotherapy in selecting eligible trials, including the study conducted by NSCLC Meta-analyses Collaborative Group.19 For the reasons mentioned above, trials with postoperative radiotherapy were excluded from our meta-analysis to avoid accumulated harmful effects.

It should be noted that publication bias is a potential threat to the validity of our meta-analysis. Heterogeneity decreased after excluding studies by Endo et al11 and Roselli et al14 from the overall DFS analysis; Roselli et al14 and Felip et al36 from stage I analysis; and Strauss et al35 and Felip et al36 from cisplatin-based chemotherapy analysis. The 5-year OS rate of control group was 75% in the study by Endo et al11 which was higher than the expected survival rate (50%) due to the majority of IA patients. So, the number of eligible cases (n=122) in trial design was too small to detect a difference. The study by Felip et al36 was conducted in several centers and the compliance was only 51%. The study by Strass et al35 stopped before pre-assignment time. In addition, a subset of the patients underwent minimal resection but not complete resection in the study by Roselli et al.14 Additionally, these trials that had large age difference with others were excluded from overall heterogeneity analysis. The value of I2 was still >50% after excluding studies with minimum29 and maximum age,14 and two studies with age <60 years.29,33 Therefore, age did not substantially influence heterogeneity of DFS. These factors may explain the different results among the studies.

Several limitations in this meta-analysis should be pointed out. Firstly, heterogeneity existed in some of the DFS results. Some factors, such as variable ethnic origin, TNM stage, age, and drug administration, could explain some of the difference among the studies. Secondly, we confirmed the superiority of postoperative chemotherapy alone in early stage NSCLC patients, but only 51%–86% of patients completed their predesigned chemotherapy regimens and there was an obvious gap of compliance among all trials. Further efforts to improve compliance without increasing toxicities are essential. Lastly, only articles published in full papers and English language were included in this meta-analysis. This selection might induce a potential publication bias, because positive studies are more likely and easier to be published than negative ones.