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ORIGINAL ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 5  |  Page : 12-16
 

A meta-analysis of erlotinib versus docetaxel for advanced nonsmall-cell lung cancer with poor prognosis


1 Department of General Surgery, Sanmen Hospital of Traditional Chinese Medicine, Sanmen 317100, India
2 The Quality Management Office, The Second Affiliated Hospital of Zhejiang University, Hangzhou 310009, China
3 Department of Thoracic Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou 310009, China

Date of Web Publication3-Nov-2015

Correspondence Address:
X Lv
Department of Thoracic Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou 310009
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.168957

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 » Abstract 

Background: The extent of the benefit of erlotinib in the treatment of advanced nonsmall-cell lung cancer (NSCLC) is still controversial when compared with docetaxel. This meta-analysis was performed to compare the efficacy of erlotinib with docetaxel for different patients with advanced NSCLC. Materials and Methods: We searched Cochrane Library, PubMed, CNKI, and identified 23 randomized controlled clinical trials from 2008 to 2015. According to our further full-text screening, 6 clinical trials were included in the final meta-analysis. Results: Six papers were included in this study. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and toxicity were included in our outcomes. The pooled hazard ratio (HR) of PFS was 1.57 (95% confidential index [CI] = 1.47–1.69). The pooled HR of OS was 1.66 (95% CI = 1.43–1.92). The pooled risk ratio of ORR was 0.56 (95% CI = 0.35–0.91). The toxicity analysis showed odds ratio = 1.79 (95% CI = 1.20–2.69). Conclusions: In terms of PFS, OS, and toxicity the effect of erlotinib in the treatment of advanced NSCLC patients is superior to docetaxel.


Keywords: Docetaxel, erlotinib, meta-analysis, nonsmall-cell lung cancer


How to cite this article:
Xu W, Jin C, Dai X, Lv X. A meta-analysis of erlotinib versus docetaxel for advanced nonsmall-cell lung cancer with poor prognosis. Indian J Cancer 2015;52, Suppl S1:12-6

How to cite this URL:
Xu W, Jin C, Dai X, Lv X. A meta-analysis of erlotinib versus docetaxel for advanced nonsmall-cell lung cancer with poor prognosis. Indian J Cancer [serial online] 2015 [cited 2021 Jul 31];52, Suppl S1:12-6. Available from: https://www.indianjcancer.com/text.asp?2015/52/5/12/168957



 » Introduction Top


Lung cancer has become the world's highest rates of morbidity and mortality of malignant tumors. It is estimated that every year in the world will have 1.4 million people diagnosed with lung cancer and had 1.2 million people die of lung cancer.[1] Classification according to the pathology and cytology, lung cancer can be divided into small-cell lung cancer and nonsmall-cell lung cancer (NSCLC) in two types with more than 80% of lung cancer NSCLC. NSCLC in patients with locally advanced lung cancer accounts for about 25%–30%; metastatic lung cancer accounts for about 40%–50%.[2] Among them, 70–85% fail to qualify for surgical treatment.[3] Patients with advanced NSCLC with good performance status can be treated with platinum-based chemotherapy. But the long-term response to first-line chemotherapy is rare. Erlotinib and docetaxel as the second-line therapies have shown similar efficacy in the therapy of advanced NSCLC patients.[4],[5],[6],[7]

Erlotinib is a competitive inhibitor of the epidermal growth factor receptor (EGFR)-associated tyrosine kinase (TK) and showed a clear survival advantage over best supportive care in patients that had failed at least one line of chemotherapy. Response to erlotinib is highly dependent on the EGFR gene mutation status and conformation of the ATP-binding domain in TK. Approval of erlotinib in second-line treatment was based on Br. 21 phase III study which has not shown an evident correlation between the presence of EGFR mutation and erlotinib efficacy.[8] Previse study discovered better overall survival (OS) with docetaxel than with erlotinib (8.2 months vs. 5.4 months, respectively; adjusted hazard ratio (HR): 0.73; 95% confidence interval [CI]: 0.53–1.00; P = 0.05), and better median progression-free survival (PFS: 2.9 months vs. 2.4 months, respectively; and adjusted HR: 0.71; 95% CI: 0.53–0.95; P = 0.02) in second-line treatment specifically targeting EGFR-wild-type NSCLC.[9] Docetaxel was the first traditional cytotoxic drug to demonstrate a clear survival advantage over best supportive care in the phase III setting for patients failing platinum-based therapy. For patients unable to tolerate platinum toxicity, need to take medicine treatment. On the second-line treatment of NSCLC and monotherapy, docetaxel is currently the only United States food and drug administration and the European Medicines Evaluation Agency license, as the gold standard for the treatment of advanced NSCLC second-line chemotherapy.[10] Docetaxel treatment of NSCLC has serious hematological toxicity will have an impact on patients with dependence.[11]

Based on the presented study, erlotinib and docetaxel are both active in NSCLC treatment, but further analysis was needed to show the best sequence in which to use these agents. Several clinical trials were conducted to compare the efficacy and toxicity of erlotinib with docetaxel. However, their results were inconsistent attributed to different inclusion and exclusion criteria. Our meta-analysis will provide more information for future research, which will help make evidence-based clinical decisions for the treatment of advanced NSCLC.


 » Materials and Methods Top


Literature search

An electronic search on the PubMed database, Cochrane Library database, and CNKI were performed. The search items were used as (“ll-cell lung cancer”). The published language included English and Chinese, and the years were limited from February 2003 to June 2015. The searching procedure was done and cross-checked by two reviews independently. All of the dates were extracted independently by two reviewers according to the selection criteria.

Inclusion criteria

Eligible references were selected carefully based on the following criteria: (1) Randomized controlled trial; (2) patients with historically or cytologically confirmed stage; (3) studies comparing the efficacy and toxicity of erlotinib with docetaxel; and (4) information collected including response rate, HR for PFS and OS, along with the 95% confidential index (CI).

Quality assessment

The Jadad scale, a 5-point scale system, was used to evaluate the methodological quality of trials, which assessed randomization (0–2 points), double-blind (0–2 points), and follow-up (0–1 points).[12] The Jadal scale has total scores ranged from 0 to 5, and clinical trials are defined as “;good” when the score is from 3 to 5.

Data extraction

Two reviewers independently extracted all the date with the use of standardized data-abstraction forms. The following information were collected from each study, although some information was not contained in some trials: Trial's name, first author, year of publication, number of patients, and patient information (median age, gender, smoking history, WHO performance status, tumor histology). Furthermore, objective response rate (ORR), median PFS and OS, HRs for PFS and OS and 95% CI, and side-effects were included.

Statistical analysis

Our analysis was performed in Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014. The pooled HRs for PFS, OS, and pooled risk ratios (RRs) for ORR were calculated. The statistical heterogeneity between trials was evaluated by the Chi-squared Q-test based on the fixed-effect model. When the P value of the Q-test was <0.1, or when I2 was >50%, it represented heterogeneous between clinical trials. Then, a random effect model was used to accommodate the heterogeneity. Furthermore, we performed the leave-one-out strategy to test the influence of each trial on the heterogeneity. However, the maximum docetaxel administration was limited to 6 cycles.


 » Results Top


Literature search

A total of 954 publications were preliminarily included after systematic database searched. Only 6 clinical trials which showed comparing the efficacy and toxicity of erlotinib and docetaxel in advanced NSCLC were included in this meta-analysis through duplicates and full-text articles excluded.[4],[5],[6],[7],[9],[13] The flow of this search strategy is shown in [Figure 1]. The basic information of the enrolled patients in 6 clinical trials, such as performance status and histological status are listed in [Table 1].
Figure 1: Diagram of the literature search and trial selection process

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Table 1: Baseline characteristics of included studies

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According to the method, all the 6 trials are multicenter, randomized, and open-label studies. Quality of these enrolled trials was scored due to Jadad's scale. 1245 patients were randomly assigned to receive either erlotinib (150 mg/day, orally, 659 patients) or docetaxel (75 mg/m 2 intravenously every 3 weeks, 586 patients). Patients enrolled in analysis should receive treatment until disease progression, intolerable toxicity, or discontinuation for another reason.

Progression-free survival

According to these 4 trials, the HRs for PFS were derived from the supportive adjusted model. The pooled HR for PFS showed significant difference between erlotinib and docetaxel group [HR = 1.57. 95% CI = 1.47–1.69, P = 0.00, [Figure 2], suggesting an erlotinib advantage over docetaxel for patients with advanced NSCLC.
Figure 2: Forest plot of comparison for progression-free survival between erlotinib and docetaxel in advanced nonsmall-cell lung cancer

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Overall survival

Due to the comparing results of 4 trails, the pooled HRs for OS showed significant difference between erlotinib and docetaxel groups [HR = 1.66, 95% CI = 1.43–1.92, P = 0.00, [Figure 3]. For OS analysis showed that erlotinib comparing docetaxel in the treatment of advanced NSCLC has obvious advantages.
Figure 3: Forest plot of comparison for the overall survival between erlotinib and docetaxel group

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Objective response rate

The pooled RRs for ORR were significantly different between erlotinib and docetaxel group [RR = 0.56, 95% CI = 0.35–0.91, [Figure 4]a, indicating docetaxel benefit in the ORR. However, there was a great heterogeneity between these two groups (I2 = 49%), although a random-effect model was performed. The influence of each individual trial on the heterogeneity was tested. After Ng's trial was excluded, it showed no heterogeneity [I2 = 0%, [Figure 5], whereas the pooled RRs for ORR exhibited no significant difference [RR = 0.32, 95% CI = 0.14–0.73, [Figure 4]b.
Figure 4: (a) Forest plot of comparison for the objective response rate between erlotinib and docetaxel group. (b) Forest plot of comparison for the objective response rate between erlotinib and docetaxel group (excluded Ng's trial)

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Figure 5: (a) Forest plot of comparison for toxicity between erlotinib and docetaxel group. (b) Forest plot of comparison for toxicity between erlotinib and docetaxel group (without Kawaguchi's trial)

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Toxicity

As expectancy, docetaxel resulted in more grades 3 or 4 common toxicity criteria than erlotinib. The pooled odds ratio (OR) was 4.92 [95% CI = 3.60–6.72, P = 0.00, [Figure 5], indicating less toxicity of erlotinib compared with docetaxel. However, a great heterogeneity (I2 = 97%) was exhibited between erlotinib and docetaxel, even though a random-effect model was performed. Kawaguchi's trial was the source of heterogeneity. After excluding the data by leave-one-out strategy of Kawaguchi's trial, I2 = 88% [OR = 1.79, 95% CI = 1.20–2.69, [Figure 5]b.


 » Discussion Top


Lung cancer is the most common malignancy, platinum combination chemotherapy NSCLC standard is the first line of treatment, but the effect has reached a plateau.[14] Most after first-line chemotherapy in advanced NSCLC patients the disease progresses to the second-line treatment. The main purpose of second-line treatments is to prolong the lifetime improve the quality of life, reducing treatment side-effects.[15] Analysis shows that the effects of gefitinib in advanced NSCLC and docetaxel are similar, but better tolerated, suggesting that gefitinib might become the preferred advanced NSCLC second-line treatment. Gefitinib and erlotinib all belongs to EGFR-TKI drugs and aimed at second-line target therapy of NSCLC, they both contributed to prevent cancer progression, spread, and mitigation. In order to evaluate the erlotinib compared with chemotherapy in treatment of second-line status, based on a number of a major meta-analysis of randomized clinical trials, we sort the results are as follows.

In this update meta-analysis, 6 clinical trials discovered that erlotinib could prolong PFS significantly with the use of supportive adjusted model [HR = 1.57, 95% CI = 1.47–1.69, P < 0.01]. This comparative analysis result are not the same as previous results in terms of PFS of NSCLC patients that these patients had a similar effect through treating by erluotini and docetaxe.[4],[5],[13] But at the subgroups analysis showed improved benefit from erlotinib therapy compared with docetaxel treatment.[4] Therefore, erlotinib can effectively extend the PFS of NSCLC patients by targeting EGFR mutation. Moreover, erlotinib showed an obviously advantage in OS compared with docetaxel treatment, and this result was caused by the cross-over to alternative therapy at disease progression, so we can detect an OS benefit for patients who received erlotinib treatment showing better than docetaxel treatment, respectively. However, patients treated with erlotinib showed equivalent ORR as docetaxel group [RR = 0.32, 95% CI = 0.14–0.73, P = 0.63]. Previous studies have pointed out that erlotinib and gefitinib in the treatment of NSCLC patients individually show the similar ORR,[16] and gefitinib and docetaxel in patients with NSCLC treated individually also showed the similar ORR.[4] In terms of toxicity, due to the inclusion documentation of information extraction, only Garessino's trial and Krawczyk's trial were considered for comparison eventually. The result indicated that erlotinib showing obliviously superiority compared with docetaxel (OR = 1.79, 95% CI = 1.20–2.69, P = 0.004). As a case reported that some nonsmall-cell lung cancer patients experiencing toxicities might have a good tumor response using erlotinib monotherapy.[17] According to ORR and toxicity results, we believe that the use of erlotinib in patients with NSCLC may safer and more efficient than docetaxel treatment.

For clinical factors, such as smoking, sex, performance status are implied as predictors as PFS, OS in advanced NSCLC patients.[18] In the trials, the efficacy was compared between erlotinib and docetaxel in one trial.[4],[9] One trials among which consistently reported EGFR played a critical role in treatment of erlotinib or docetaxel, and they showed that no significant difference in PFS and OS when comparing erlotinib and docetaxel in EGFR-unselected patients with NSCLC, but docetaxel was superior to erlotinib in terms of PFS and ORR in patients with EGFR wild-type disease.[5] Erlotinib was not better than docetaxel in any of the compared group analysis including those of nonsmokers and wild-type KRAS careers.[9] But not all trials show a difference in PFS, OS, or response rate for patients treated with either erlotinib or docetaxel. Although it achieved better survival and response rates in patients treated with erlotinib, the difference did not reach statistical significance after excluded Ng's trials. Based on this result, it is urgently needed more clinical trials to compare the objective of erlotinib with docetaxel in a selected population according to different clinical factors.


 » Conclusion Top


In this meta-analysis, we performed a high efficacy and longer PFS and OS of erlotinib than docetaxel, although similar ORR. In terms of toxicity, erlotinib still shows an advantage than docetaxel. Therefore, erlotinib is a potential and valid treatment alternative for patients with advanced NSCLC with poor prognosis. With the development of biomarkers prediction, clinical factors should be introduced into the analysis for more confirmative results and better-personalized medication.


 » Acknowledgments Top


This study was supported by Foundation of Zhejiang Technology Committee (2015C33123).

 
 » References Top

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Krawczyk P, Kowalski DM, Wojas-Krawczyk K, Mlak R, Jaskiewicz P, Kucharczyk T, et al. The qualification of docetaxel or erlotinib for second-line therapy should be based on clinical and molecular predictive factors. Chemotherapy 2012;58:60-9.  Back to cited text no. 4
    
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Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, et al. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA). J Clin Oncol 2014;32:1902-8.  Back to cited text no. 5
    
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Ng R, Loreto M, Lee R, Leighl NB. Brief report: Retrospective review of efficacy of erlotinib or gefitinib compared to docetaxel as subsequent line therapy in advanced non-small cell lung cancer (NSCLC) following failure of platinum-based chemotherapy. Lung Cancer 2008;61:262-5.  Back to cited text no. 7
    
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Garassino MC, Martelli O, Broggini M, Farina G, Veronese S, Rulli E, et al. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): A randomised controlled trial. Lancet Oncol 2013;14:981-8.  Back to cited text no. 9
    
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Lange A, Prenzler A, Frank M, Golpon H, Welte T, von der Schulenburg JM. A systematic review of the cost-effectiveness of targeted therapies for metastatic non-small cell lung cancer (NSCLC). BMC Pulm Med 2014;14:192.  Back to cited text no. 10
    
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Aoki T, Ebihara A, Yogo Y, Suemasu K, Sakamaki F. Analysis of continuous first-line treatment with docetaxel and carboplatin for advanced non-small cell lung cancer. Oncol Lett 2014;7:1771-7.  Back to cited text no. 11
    
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Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials 1996;17:1-12.  Back to cited text no. 12
    
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Ma K, Cohen V, Kasymjanova G, Small D, Novac K, Peterson J, et al. An exploratory comparative analysis of tyrosine kinase inhibitors or docetaxel in second-line treatment of EGFR wild-type non-small-cell lung cancer: A retrospective real-world practice review at a single tertiary care centre. Curr Oncol 2015;22:e157-63.  Back to cited text no. 13
    
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Chen LK, Liang Y, Yang QY, Xu F, Zhou NN, Xu GC, et al. Triplet platinum-based combination sequential chemotherapy improves survival outcome and quality of life of advanced non-small cell lung cancer patients. Asian Pac J Cancer Prev 2012;13:1863-7.  Back to cited text no. 14
    
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Douillard JY, Shepherd FA, Hirsh V, Mok T, Socinski MA, Gervais R, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: Data from the randomized phase III INTEREST trial. J Clin Oncol 2010;28:744-52.  Back to cited text no. 15
    
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Burotto M, Manasanch EE, Wilkerson J, Fojo T. Gefitinib and erlotinib in metastatic non-small cell lung cancer: A meta-analysis of toxicity and efficacy of randomized clinical trials. Oncologist 2015;20:400-10.  Back to cited text no. 16
    
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Jin F, Zhu H, Kong L, Yu J. A spectrum of cutaneous toxicities from erlotinib may be a robust clinical marker for non-small-cell lung therapy: A case report and literature review. Onco Targets Ther 2015;8:943-6.  Back to cited text no. 17
    
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Li R, Lou YQ, Zhang YW, Shi CL, Xiong LW, Gu AQ, et al. Clinical analysis of gefitinib in the treatment of stage iv lung adenocarcinoma with unknown egfr gene mutations. Thoracic Cancer 2013;4:433-9.  Back to cited text no. 18
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
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