CRD summary

This generally well-conducted review concluded that cetuximab plus chemotherapy was more effective than chemotherapy alone in patients with advanced non-small cell lung cancer. Marginal benefits were observed with tyrosine kinase inhibitors plus chemotherapy, although erlotinib may be beneficial in patients who have never smoked. The authors’ conclusions reflect the evidence, but the clinical meaningfulness of results is uncertain.

Authors' objectives

To assess epidermal growth factor receptor-targeted therapies plus chemotherapy versus chemotherapy alone for treating advanced non-small cell lung cancer in adult patients.

Searching

PubMed (to July 2010), EMBASE (1980 to July 2010) and the Cochrane Central Register of Controlled Trials (issue 7, 2010) were searched for articles in any language. Search terms were reported. Reference lists of relevant studies were also searched.

Study selection

Randomised controlled trials (RCTs) in adult patients (aged 18 years or older) with advanced non-small cell lung cancer that were treated with epidermal growth factor receptor-targeted therapies plus chemotherapy versus chemotherapy alone were eligible for inclusion. Trials had to report at least one of the following outcomes: overall survival, progression-free survival, overall response rate, one-year survival rate, or grade 3/4 adverse events (such as rash, diarrhoea, vomiting and neutropenia). Trials in patients that were previously exposed to epidermal growth factor receptor-targeted therapies or radiotherapy were excluded.

The included trials studied the use of the monoclonal antibody cetuximab and tyrosine kinase inhibitors (including erlotinib, gefitinib and vandetanib) in combination with platinum-based doublet chemotherapy (based on combinations of gemcitabine, paclitaxel, vinorelbine, docetaxel with carboplatin or cisplatin) versus platinum-based doublet chemotherapy alone. All therapies were administered as first-line treatments. Most trials were multi-centred. Included trials were published from 2004 to 2010. The mean age of included patients ranged from 57 to 66 years.

Two reviewers independently performed study selection, which was checked by a third reviewer.

Assessment of study quality

Two authors independently assessed trial quality using the Jadad scale, which appraised randomisation, blinding, allocation concealment, and withdrawals and drop-outs. Disagreements between reviewers were resolved by discussion.

Data extraction

Two reviewers independently extracted data on overall survival and progression-free survival. These were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Relative risks (RRs) were calculated for overall response rate, one-year survival, and adverse events. Where survival data was not reported, data were taken from survival curves.

Methods of synthesis

A fixed-effects meta-analysis was used to calculate pooled hazard ratios and relative risks, together with 95% confidence intervals. If statistical heterogeneity was detected, a random-effects meta-analysis was used. Heterogeneity was assessed using I² and X² (p value set at 0.05).

The data were analysed separately for tyrosine kinase inhibitors and monoclonal antibodies.

Subgroup analysis was conducted for erlotinib in patients who had never smoked. Sensitivity analyses were conducted on trial quality and sample size.

Results of the review

Ten RCTs were included in the review (n=5,936 patients). The quality of the included trials was variable; three scored 5 out of 5 points, two scored 4, four scored 3, and one scored 2. None of the trials reported randomisation or the method of allocation concealment. Half of the trials were open-label or did not mention blinding. Median follow-up ranged from 15.9 to 23.8 months.

Cetuximab plus platinum-based doublet chemotherapy (four RCTs; n=2,018 patients): There was a statistically significant increase in overall survival (0.87, 95% CI 0.78 to 0.96; I²=0%; four RCTs), a marginally prolonged progression-free survival (HR 0.91, 95% CI 0.82 to 1.00; I²=0%; four RCTs), an improvement in overall response rate (RR 1.32, 95% CI 1.15 to 1.52; I²=0%; four trials), and an increase in one-year survival (RR 1.13, 95% CI 1.02 to 1.24; I²=0%; four RCTs) for chemotherapy plus cetuximab compared with chemotherapy alone. For adverse events, there were statistically significantly higher risks for rash, diarrhoea, and neutropenia with cetuximab plus chemotherapy than with chemotherapy alone.

Tyrosine kinase inhibitors plus platinum-based doublet chemotherapy (six RCTs; n=3,918 patients): There was no difference in the overall survival rate or one-year survival rate with tyrosine kinase inhibitors plus chemotherapy than with chemotherapy alone. However, there was a marginally prolonged progression-free survival (HR 0.87, 95% CI 0.76 to 0.99; I²=68%; six RCTs) and a slight improvement in overall response rate (RR 1.10, 95% CI 1.00 to 1.20; I²=0%; RCTs) with tyrosine kinase inhibitors plus chemotherapy. There was a significant benefit for the tyrosine kinase inhibitor erlotinib plus chemotherapy versus chemotherapy alone for progression-free survival in patients who had never smoked (HR 0.45, 95% CI 0.31 to 0.66; two RCTs) for the combined treatment. For adverse events, there were statistically significantly higher risks of rash and diarrhoea with tyrosine kinase inhibitor treatment. Sensitivity analysis that excluded the small low quality trial reduced the heterogeneity for progression-free survival.

Authors' conclusions

Cetuximab plus chemotherapy was more effective than chemotherapy alone in patients with advanced non-small cell lung cancer. Marginal benefits were observed with tyrosine kinase inhibitors plus chemotherapy, although erlotinib may be beneficial in patients who have never smoked.

CRD commentary

Inclusion criteria for the review were clearly defined. Several relevant data sources were searched with no language restrictions. Publication bias was not assessed and could not be ruled out. Attempts were made to reduce reviewer error and bias throughout the review process.

Quality assessment was undertaken using a standard checklist, which indicated the variable quality of the included evidence; none of the trials stated the method of allocation concealment or randomisation, which the authors acknowledged. Trials were combined using meta-analysis; statistical heterogeneity was assessed and explored in sensitivity analyses, which was appropriate. However, the clinical significance of outcomes was not fully explored.

The review was generally well conducted and the authors’ conclusions reflect the evidence, but the clinical meaningfulness of results is uncertain.

Implications of the review for practice and research

Practice: The authors stated that cetuximab plus platinum-based doublet chemotherapy should be recommended in patients with advanced non-small cell lung cancer. Erlotinib may be beneficial for patient who had never smoked.

Research: The authors stated that more research was required to gain a clear understanding why patient who had never smoked gained benefit from erlotinib. They also stated that further research was needed to determine why addictive effects were not seen with the addition of tyrosine kinase inhibitors to platinum-based doublet chemotherapy.

Funding

Not stated.

Bibliographic details

Chen P, Wang L, Liu B, Zhang HZ, Liu HC, Zou Z. EGFR-targeted therapies combined with chemotherapy for treating advanced non-small-cell lung cancer: a meta-analysis. European Journal of Clinical Pharmacology 2011; 67(3): 235-243. [PubMed: 21207017]

Original Paper URL

http://onlinelibrary.wiley.com/doi/10.1111/j.1463-1318.2009.02015.x/abstract

Indexing Status

Subject indexing assigned by NLM

MeSH

Antibodies, Monoclonal /administration & dosage; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols /adverse effects /pharmacology /therapeutic use; Carcinoma, Non-Small-Cell Lung /drug therapy /physiopathology; Disease-Free Survival; Drug Delivery Systems; Humans; Lung Neoplasms /drug therapy /physiopathology; Protein Kinase Inhibitors /administration & dosage; Randomized Controlled Trials as Topic; Receptor, Epidermal Growth Factor /antagonists & inhibitors; Survival Rate; Treatment Outcome

AccessionNumber

12011002949

Database entry date

02/11/2011

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.