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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 1  |  Page : 139-144

Meta-analysis of adjuvant chemotherapy versus surgery alone in T2aN0 stage IB non-small cell lung cancer


1 Department of Thoracic Surgery, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China
2 Department of Emergency Room, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China
3 Department of Pharmacology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China

Date of Web Publication8-Mar-2018

Correspondence Address:
Dr. Shaofa Xu
Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing - 101 149
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_862_17

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 > Abstract 

Background: Although there is a strong evidence that adjuvant chemotherapy after surgery was effective in Stages II and IIIA patients involved nonsmall cell lung cancer (NSCLC), its eligibility in Stage IB disease has been unknown. Therefore, this meta-analysis was aimed to compare the effects of adjuvant chemotherapy versus surgery alone in patients with Stage IB NSCLC.
Materials and Methods: We systematically searched for articles from their inclusion to July 2016. An article search was performed in PubMed, Embase, Medline, and Cochrane Library. Irrelevant literature was excluded with the preferred reporting items for systematic reviews and meta-analysis standards. Overall survival (OS) was the primary end-point, which was defined as the time from randomization until death from any cause; our second end-point was disease-free survival (DFS). All analyses were based on intention-to-treat.
Results: Six randomized controlled trials with total of 2007 patients were included in present meta-analysis. The results were expressed as risk ratios (RR) with 95% confidence intervals (CIs). Compared to surgery alone, patients can benefit from adjuvant chemotherapy after surgery in terms of 5-year OS (RR = 1.19; 95% CI, 1.03–1.37; P = 0.02) and 5-year DFS (RR = 1.36; 95% CI, 1.13–1.63; P = 0.001). There was no significant difference in terms of benefit according to certain patient characteristics, such as age, gender, tumor histology, smoking history, and resection type.
Conclusion: Adjuvant chemotherapy after surgery was beneficial to the patients with Stage IB disease in terms of OS and progression-free survival. Therefore, we recommend clinicians to take this treatment strategy into account for the patients with Stage IB NSCLC.

Keywords: Adjuvant chemotherapy, Stage IB nonsmall cell lung cancer, surgery alone


How to cite this article:
Zhang T, Guo Q, Zhang Y, Liu Z, Zhou S, Xu S. Meta-analysis of adjuvant chemotherapy versus surgery alone in T2aN0 stage IB non-small cell lung cancer. J Can Res Ther 2018;14:139-44

How to cite this URL:
Zhang T, Guo Q, Zhang Y, Liu Z, Zhou S, Xu S. Meta-analysis of adjuvant chemotherapy versus surgery alone in T2aN0 stage IB non-small cell lung cancer. J Can Res Ther [serial online] 2018 [cited 2019 Nov 15];14:139-44. Available from: http://www.cancerjournal.net/text.asp?2018/14/1/139/226769


 > Introduction Top


Lung cancer is the leading cause contributed to cancer-relevant death worldwide, with an estimated 1.8 million new cases diagnosed in 2012.[1] Roughly, 85% of all reported lung cancer patients involved nonsmall cell lung cancer (NSCLC). Less than 20% of patients diagnosed with NSCLC would be candidates for potentially curative resection. Although the mainstay of treatment for early-stage NSCLC has been complete surgical resection with mediastinal lymph node dissection, the overall survival (OS) for pathologically staged IB NSCLC remained low, at approximately 60%.[2],[3] As a result, more effective treatment strategies are urgently required to reduce lung cancer mortality and recurrence rate.

Many randomized clinical trials have reported the efficacy of surgery followed by platinum-based adjuvant chemotherapy in Stage II-IIIA lung cancer.[4],[5],[6] The efficacy of platinum-based adjuvant chemotherapy in Stage IB NSCLC has been also studied in six randomized controlled trials (RCTs).[6],[7],[8],[9],[10],[11] However, adjuvant chemotherapy has not been currently a standard treatment for Stage IB NSCLC and the benefit of adjuvant chemotherapy remained controversial for patients with resected Stage IB NSCLC. Therefore, a meta-analysis was conducted on published RCTs to quantitatively evaluate the survival benefit of patients who received the two regimens.


 > Materials and Methods Top


Eligibility criteria

Adjuvant chemotherapy was defined as chemotherapy administered after surgery. Chemotherapy strategy should be platinum-based and similar to adjuvant chemo group. Surgery alone was defined as wedge resection, lobectomy, and pneumonectomy. RCTs were conducted to compare adjuvant chemotherapy after surgery with surgery alone, with the preferred reporting items for systematic reviews and meta-analysis standards,[12] as the basis for reporting the materials and methods of this study.

Following eligibility criteria for our meta-analysis were set before collecting the articles: (i) RCTs; (ii) patients involved in the trails were Stage IB NSCLC based on the sixth (same as fifth edition) and seventh international staging criteria;[13],[14] (iii) the survival data provided in the articles could be applied to calculate the survival and risk-related data at specific time intervals, for the patients who received adjuvant chemotherapy and surgery alone after surgery; and (iv) median follow-up time of the study should be at least 3 years.

Search strategy

Published and unpublished trials were performed in PubMed, Embase, Medline, and Cochrane Library from the inclusion to July, 2016. The RCTs were identified with the Cochrane collaboration optimal search strategy without language restriction. To achieve the maximum sensitivity, the search strategy was conducted with following keywords: “lung cancer” AND “NSCLC” OR “Stage IB” AND “nonsmall-cell lung carcinoma” AND “chemotherapy, adjuvant” OR “postoperative chemotherapy.” All the articles were screened according to the inclusion and exclusion criteria.

Data extraction

The data of eligible trials were independently extracted with two investigators, and discrepancies between investigators were resolved through the discussion. Non-English publications were evaluated on their English abstract and the translation of their main text. Totally 594 citations were identified and unrelated articles were excluded from the study. Finally, only six trials [6],[7],[8],[9],[10],[11] met all requirements of our eligibility criteria [Figure 1]. Study characteristics (study duration, surgery regimen, and median follow-up) and patient characteristics (age, gender, tumor histology, smoking history, and resection type) were also recorded [Table 1] and [Table 2].
Figure 1: Flow diagram. Selection and evaluation process of the eligible studies

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Table 1: Characteristics of included randomized clinical trials of adjuvant chemotherapy versus surgery alone

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Table 2: Patient characteristics

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Validity assessment

The quality of RCTs was independently assessed by two investigators, and the discrepancies were resolved by consensus. Using the Cochrane approach to analyze the allocation concealment, the trials were described as having adequate, unclear, or inadequate concealment.[15] The investigators evaluated whether there was blinding of outcome assessment and adequate description of withdrawals.[16] The adequacy of the randomization method was assessed as previously described by Jadad et al.[16] Finally, an assessment was made as to whether intention-to-treat analysis was applied in the trial results.[17],[18] The authors of the included trials were asked to verify the assessments of study methodology where possible.

Statistical analysis

The primary end-point was OS, and the second end-point was disease-free survival (DFS). Surviving patients were censored at the date of the last follow-up. The survival rates were derived from the published survival curves if it was not provided explicitly in the text or tables. Data extraction from the survival curves was independently performed by two investigators, and the mean measured values were applied for the meta-analysis. Statistical analyses for the meta-analysis were performed with RevMan (Review Manager Version 5.3 for Windows, Cochrane Collaboration. Oxford, UK, 2014), and a pooled relative risk was calculated with 95% confidence intervals (CIs). Analyses were stratified by trials. To undertake a random-effects meta-analysis, the standard errors of the study-specific estimates were adjusted to incorporate a measure of the extent of variation, or heterogeneity, among the treatment effects observed in different studies. Chi-square heterogeneity tests were applied to test for statistical heterogeneity among trials. The I 2 statistics were also applied to assess the proportion of variability in the results attributable to heterogeneity across studies, and I2< 25%, 25% ≤ I2< 50%, and I2 > 50% or more was interpreted as signifying low-level, intermediate-level, and high-level heterogeneity, respectively.[15] Analyses by patient characteristics were performed to study the interaction between the treatment effect and following characteristics: age, gender, tumor histology, smoking history, and resection type. All P values were two-sided. P < 0.05 was considered to indicate statistically significant difference.


 > Results Top


Study characteristics

Totally six RCTs were identified, and 2007 patients were involved, which investigated the survival of Stage IB NSCLC patients treated with adjuvant chemotherapy after surgery. All six trials reported mature data on survival benefit whereas two trials also included patients with IB-IIIA and IB-II.[6],[8] The OS and DFS of Stage IB patients could not be obtained in these two trials. Thus, their survival rates were not included in our meta-analysis, but the patient characteristics in those two trials were available. Our meta-analysis on OS and DFS was only based on four trials with 685 patients who were randomly assigned. The analyses of patient characteristics were based on all six trials.

Treatment regimens

In all these trials, platinum-based chemotherapy combined with one other drug (etoposide, paclitaxel, or vinorelbine) was applied as adjuvant chemotherapy after surgery. Surgery alone included wedge resection, lobectomy, and pneumonectomy. The trial characteristics were summarized in [Table 1]. There was no significant difference between the two treatments according to certain patient characteristics, such as age, gender, tumor histology, smoking history, and resection type, in terms of benefit [Table 2].

Study quality

The quality of the included trials was shown [Figure 2]a and [Figure 2]b. The included trials were found to have an unclear allocation concealment except for one trial.[7] In addition, most of included trials were conducted with a method of adequate randomization apart from one trial.[10] The analyses of all the trials were by intention-to-treat. Three trials clearly pointed out blinded assessment of outcome,[8],[9],[11] whereas the remaining three trials did not describe the assessment method of outcome. According to the methodological quality of six trials, author's judgement regarding each risk of bias item was reviewed [Figure 2]a and [Figure 2]b.
Figure 2: (a) Risk of bias graph: each risk of bias item presented as percentages across all included studies (b) risk of bias summary: review authors' judgments about each risk of bias item for each included study

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Survival analysis

This meta-analysis was performed to compare the adjuvant chemotherapy to surgery alone by estimating the risk ratios (RR) of OS and DFS. The survival analysis was based on four trials with 685 patients. Adjuvant chemotherapy after surgery was beneficial to the patients with Stage IB disease in terms of OS (RR = 1.19; 95% CI, 1.03–1.37; P = 0.02) and 5-year DFS (RR = 1.36; 95% CI, 1.13–1.63; P = 0.001), respectively [Figure 3]a and [Figure 3]b. According to the result of Chi-square heterogeneity tests, it showed a high-level heterogeneity with an I 2 value of 80% (Chi-square tests for heterogeneity P = 0.002) and 79% (also, P = 0.002). Data analysis which was available for patient characteristics showed that there was no significant difference between the two treatments according to certain patient characteristics [Table 2].
Figure 3: (a) Five-year overall survival. I2 test for heterogeneity; P = Chi-square distribution test for heterogeneity with rejection region = 0.1; CI = Confidence interval (b) 5-year disease-free survival. I2 test for heterogeneity; P = X2 distribution test for heterogeneity with rejection region = 0.1; CI = Confidence interval

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 > Discussion Top


Curative surgical resection has been considered as standard treatment for providing survival benefits for early-stage NSCLC, especially for those patients without distant lymph nodal involvement.[19] However, previous clinical trials have shown that the long-term survival was not satisfactory, and the recurrence rate was quite high even in the case of radical surgery.[20],[21],[22] The 5-year survival rates of patients undergoing complete surgical resection was merely 40%–60%.[2],[3] The poor long-term prognosis was likely due to locoregional progression and distant recurrences. Shi [23] reported in their study that increased osteopontin protein expression may be correlated with poor prognosis in NSCLC. For all these reasons, many clinical trials have been presently carrying to assess the real impact of adjuvant chemotherapy on DFS and OS of NSCLC patients.[24],[25],[26],[27],[28],[29],[30] Although positive benefit was reported in many of these clinical trials for Stage IB disease with adjuvant chemotherapy, there was no clear evidence in terms of conferring survival benefits compared with surgery alone for Stage IB NSCLC patients. Against this background, we performed a meta-analysis to assess the efficacy of adjuvant chemotherapy after surgery versus surgery alone in the treatment of Stage IB NSCLC.

In the 1995 year, NSCLC Collaborative Group performed a meta-analysis, which showed a nonsignificant absolute increase of 5% in the 5-year survival rate with the cisplatin-based adjuvant chemotherapy (without postoperative radiotherapy).[31] Based on this meta-analysis, the International Adjuvant Lung Cancer Trial was designed to evaluate the effects of cisplatin-based adjuvant chemotherapy on survival after complete resection of NSCLC.[4] Their results strongly supported the use of three or four cycles of cisplatin-based adjuvant chemotherapy after radical resection in patients with NSCLC.[4] To further confirm the efficacy of adjuvant chemotherapy after surgery, we selected RCTs of adjuvant chemotherapy versus surgery alone for the treatment of Stage IB NSCLC. According to our meta-analysis, it revealed significant survival benefit in terms of 5-year OS (RR = 1.19; 95% CI, 1.03–1.37; P = 0.02) and 5-year DFS (RR = 1.36; 95% CI, 1.13–1.63; P = 0.001) with adjuvant chemotherapy. Our results match with the findings from the results reported by the International Adjuvant Lung Cancer Trial.[4]

To the best of our knowledge, this study has been the first meta-analysis on adjuvant chemotherapy followed by surgery versus surgery alone, including six complete RCTs. Although a meta-analysis performed by He et al.[32] demonstrated that 6-cycle platinum-based chemotherapy can improve OS and DFS in Stage IB NSCLC, their analysis included a lot of patients who were not in nonstage IB NSCLC. We considered that it may increase overall heterogeneity of meta-analysis, lead to an indefinite conclusion. However, our meta-analysis included six high qualified RCTs, and the patients were in Stage IB NSCLC. This way, treatment heterogeneity may be lowered to the minimum degree. Collectively, our meta-analysis provided clinicians with highly persuasive evidence that the survival benefit of adjuvant chemotherapy after surgery was moderate. Nevertheless, several thoracic surgeons still treated Stage IB NSCLC patients with surgery alone. It suggested that clinicians reached a plateau in survival benefit with current treatment (surgery alone) against Stage IB NSCLC.

The heterogeneity test detected high heterogeneity (I 2 = 80% and 79%, P = 0.002). We found that it was due to the results published by Hung et al.[10] The method of randomization of their trial was inadequate. In addition, the adjuvant chemotherapy used in their trial was not strictly platinum-based therapy. Although we included such a low qualified trial in our meta-analysis, it had no impact on our results, for the following reasons: (i) Jung's trial only accounted for a weight of 6.9% and 5.3% for OS and DFS, respectively, suggesting that even if this included trial was omitted, our consequence may not be definitely affected and (ii) five high qualified RCTs were included in this meta-analysis, which increased the confidence level of this study.

Limitation

There were several potential limitations in this study. First, the patients involved in our study were diagnosed as Stage IB NSCLC on the sixth or the seventh international staging criteria. The staging criteria we used in the study were adopted due to the following reasons: (i) our study was designed and conducted before the publication of the eighth international staging criteria;[33] (ii) the RCTs referring to OS and DFS often lasted for a relatively long time, and the designers of those trails had applied the staging criteria during their studies; (iii) the Stage IB NCSLC in fifth and sixth international staging criteria was “tumor with any of the following features (size or extent): >3 cm in greatest dimension; involved main bronchus, ≥2 cm distal to the carina; invaded the visceral pleura; associated with atelectasis or obstructive pneumonitis that extended to the hilar region but did not involve the entire lung,”[13] and the Stage IB NCSLC in seventh edition was “tumor >3 cm but ≤5 cm in greatest dimension; involved main bronchus, ≥2 cm distal to the carina; invaded the visceral pleura; associated with atelectasis or obstructive pneumonitis that extended to the hilar region but did not involve the entire lung.”[14] From those two criteria, we could see that the criterion of IB NSCLC in seventh edition was included in the sixth criterion. Second, all the trials involved in this meta-analysis were conducted on the fifth and sixth edition except one trail,[10] which may influence the heterogeneity of this study. Another potential limitation was that our meta-analysis was unable to acquire the original data from the included studies.

The eighth international staging criteria were published in January 2017,[33] our subsequent studies will focus on the OS and DFS of the patients meeting the current staging criteria. We also look forward to more RCTs that study the effects of adjuvant chemotherapy in patients suffering Stage IB NSCLC.


 > Conclusion Top


Adjuvant chemotherapy after surgery, as compared with surgery alone, can definitely improve the OS and progression-free survival rates. In other words, distant survival could be prolonged with adjuvant chemotherapy due to decreasing locoregional progression and distant recurrences. Thus, we positively recommend that this treatment strategy should be considered in the patients with Stage IB NSCLC.

Financial support and sponsorship

This study was supported by funding obtained from Beijing Municipal Administration of Hospitals Ascent Plan, Code: DFL20151501.

Conflicts of interest

There are no conflicts of interest.

 
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