Lung cancer is the most common malignant tumor and the leading cause of cancer-related death in the world.1 More than 1.5 million new cases of lung cancer are diagnosed every year, approximately 80% of which are non-small cell lung cancer (NSCLC).2 The morbidity is rapidly increasing mainly due to environmental pollution and unhealthy lifestyles (eg, smoking, occupational exposure, diet).3 Although surgery is the recommended treatment for NSCLC, only one-third of patients are suitable for surgery when they are diagnosed.4 Unfortunately, 5-year overall survival (OS) rate of all stages is approximately 11%–15%.5,6 Even among early stage (I/II) NSCLC patients who only undergo surgical resection, the 5-year OS rate is just 45.1%.7 These rates indicate that postoperative treatment strategies (eg, chemotherapy, radiotherapy) are essential to improve NSCLC patients’ prognosis.
Chemotherapy plays a crucial role in comprehensive NSCLC therapy. Currently, cisplatin-based drugs are the most widely used chemotherapy medicine for NSCLC. Additionally, tegafur–uracil (UFT) is another oral chemotherapy agent popular in Japan because it is associated with mild toxicity. It has been demonstrated that chemotherapy regimens based on these two drug types can significantly improve the prognosis of advanced stage (III/IV) NSCLC patients.8–10 However, whether they are beneficial for early stage (I/II) NSCLC patients still remains controversial, especially for stage I patients.10–15 For instance, the updated NCIC-JBR1015 data with a median follow-up of 9.3 years demonstrated that cisplatin-based chemotherapy improved the survival of stage IB–II patients by 11%, and subgroup analysis showed that the survival advantage was maintained in stage II patients, but not in stage IB disease. But trials conducted by Roselli et al14 indicated that postoperative cisplatin-based chemotherapy significantly improved survival of stage IB patients. Similarly, randomized controlled trials (RCTs) on postoperative chemotherapy with UFT performed by the North-east Japan Study Group for Lung Cancer Surgery (NJSG)11 and Japan Lung Cancer Research Group (JLCRG)12 also reached opposing conclusions.
Radiotherapy is also a widely used technology in cancer treatment. A previous meta-analysis16 showed that postoperative radiotherapy had a detrimental effect on survival. However, most of the current studies combined chemotherapy and radiotherapy simultaneously, such as the famous ALPI17 and IALT18 studies. The only study on postoperative chemotherapy alone was conducted by NSCLC Meta-analyses Collaborative Group and utilized many outdated regimens.19 Therefore, the effect of modern postoperative chemotherapy alone in NSCLC is unclear. Herein, we performed a new meta-analysis to investigate the survival benefits conferred by adjuvant chemotherapy without radiotherapy in early stage NSCLC patients.
PATIENTS AND METHODS
Search strategy and eligibility criteria
Eligible RCTs that compared surgery plus postoperative chemotherapy versus surgery alone and published in English language were identified by searching the PubMed (http://www.ncbi.nlm.nih.gov/pubmed), Embase (http://www.embase.com/info/helpfiles/), and Science Direct (http://www.elsevier.com/online-tools/sciencedirect) databases. We also manually searched the reference lists of relevant meta-analyses and reviews. The keywords included: “non-small cell lung cancer”, “surgery”, “resection”, “lobectomy”, “pleurectomy”, “chemotherapy”, “adjuvant”, “therapy”, “early”, “I”, “II”, “1”, “2”, and “random*”. Eligible patients had to meet the following criteria: 1) histologically confirmed NSCLC (including adenocarcinoma, squamous cell carcinoma, and large cell carcinoma) with radically resection; 2) pathologic stage I and/or II with an Eastern Cooperative Oncology Group performance status of 2 or less; 3) no major organ (liver, kidney, or heart) dysfunction; 4) no preoperative anticancer treatment; 5) no other cancer site besides lung; and 6) randomly assigned to surgery followed by adjuvant chemotherapy (chemotherapy group) and surgery alone (control group). Trials that evaluated other adjuvant therapies (radiotherapy, endocrine therapy, and immunotherapy) and neoadjuvant therapy were excluded from this meta-analysis. To update the data, RCTs published in a previous meta-analysis20 in 1995 were excluded from this study; only RCTs published after January 1, 1992 were enrolled.
Two reviewers (Yuan-Yuan Chen and Lin-Wei Wang) independently extracted the following data from each enrolled trial: publication year, first author, pathologic stage, median follow-up time, treatment compliance, number of patients, chemotherapy regimen, and toxicity data. If provided in the trial, the P-value and hazard ratio (HR) at 5 years obtained from Cox regression model were used directly in this meta-analysis. If not available, approximations of HR estimates were indirectly calculated based on the correlative statistics (number of observed and total events, P-value, 95% confidence interval [CI]) using the methods described by Tierney et al.21 Alternatively, data was extracted from published Kaplan–Meier curves. To further analyze the effects of prognostic factors on survival, subgroup analyses were carried out according to pathologic stage and adjuvant therapy type. Any discrepancy was resolved by discussing with another author (Bi-Bo Wu).
The quality of the included RCTs was evaluated using the Cochrane Collaboration’s risk of bias tool,22 which included adequate sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other bias. Each item was classified as low, high, and unclear risk of bias, and then a summary assessment of each included trial was graded as A, B, or C. Two reviewers concurrently checked the risk of bias.