Home > DARE Reviews > Maintenance therapy with continuous or...

PubMed Health. A service of the National Library of Medicine, National Institutes of Health.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Maintenance therapy with continuous or switch strategy in advanced non-small cell lung cancer: a systematic review and meta-analysis

X Zhang, J Zang, J Xu, C Bai, Y Qin, K Liu, C Wu, M Wu, Q He, S Zhang, L Wei, and J He.

Review published: 2011.

Link to full article: [Journal publisher]

CRD summary

The review concluded that maintenance therapy with either switch or continuous strategies significantly increased overall and progression-free survival compared with observation or placebo, but was associated with increased toxicities. The review was well conducted and the authors' conclusions were based on generally high-quality studies and are likely to be reliable.

Authors' objectives

To compare the efficacy (survival) and safety (adverse events) of maintenance treatment with observation or placebo in patients with advanced non-small cell lung cancer (NSCLC).

Searching

PubMed, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) were searched up to August 2010. There were no language restrictions. Search terms were reported. Proceedings of the annual meetings of the American Society of Clinical Oncology were searched from 1994 to 2010. World Health Organisation (WHO) database and ClinicalTrials.gov and reference lists of reviews and retrieved studies were searched.

Study selection

Randomised controlled trials (RCTs) of maintenance therapy compared with observation or placebo in patients with stage IIIb or IV NSCLC without disease progression after initial therapy were eligible for inclusion in the review. Maintenance therapy was defined as continuing with at least one of the agents in the initial therapy or switching to a different agent. The primary outcome was overall survival. Secondary outcomes were progression-free survival and toxicity. Trials were excluded if they included only patients with stage III NSCLC or if survival was not measured as an outcome.

In the included studies, median age of participants ranged from 56 to 68 years. Fifty-two per cent to 79% of participants were men. Most of the participants had stage IV disease. Continuous maintenance regimens used only the cytotoxic agent gemcitabine. Switch maintenance regimens used the cytotoxic agents (docetaxel and pemetrexed) or tyrosine kinase inhibitor agents (erlotinib and gefitinib). Control groups had placebo, observation or best supportive care.

The authors did not state how many reviewers selected studies for the review.

Assessment of study quality

Studies were assessed for quality using the five-point Jadad scale.

Two reviewers independently assessed the included studies for quality; disagreements were resolved by a third reviewer.

Data extraction

Data were extracted on rates of overall survival and progression-free survival (defined as survival from the date of randomisation) and adverse events rates (defined as drug-related WHO grade 3 or greater toxicity). Log hazard ratios (HRs) together with their variances were calculated for survival outcomes and odds ratios (ORs) together with 95% confidence intervals (CIs) were calculated for adverse events.

Two reviewers independently extracted data; disagreements were resolved by a third reviewer.

Methods of synthesis

Studies were pooled in meta-analyses and summary effect hazard ratios and odds ratios, with their 95% CIs, were estimated using a fixed-effect model (no significant heterogeneity) or a random-effects model (significant heterogeneity). Studies were analysed separately according to whether continuous or switch maintenance therapy was used. Summary effect estimates were compared using interaction tests. Heterogeneity was assessed Χ² and Ι² (p>0.1 and Ι²<25% were defined as low-level heterogeneity). Heterogeneity was explored by undertaking subgroup analyses according to the drug used. Publication bias was assessed by inspection of funnel plots and Egger's test. Sensitivity analyses were undertaken by excluding studies with low overall quality scores or trials with add-on designs.

Results of the review

Eight trials (3,736 participants) with nine pair-wise comparisons were included in the review. Seven of the eight trials were considered of high quality (Jadad score >2). Four trials were published and four were in abstract form. Median follow-up ranged from 8.3 to 20.5 months, where reported.

Efficacy: Compared with observation or placebo, switch maintenance significantly improved overall survival (HR 0.85, 95% CI 0.79 to 0.92; six trials with no significant heterogeneity) and continuous maintenance was associated with a trend suggesting improved overall survival (HR 0.88, 95% CI 0.74 to 1.04; three trials with no significant heterogeneity). The interaction test suggested that there was no difference between continuous and switch maintenance therapy (interaction P=0.77). Compared with observation or placebo, both maintenance therapies were associated with significantly greater progression-free survival (switch HR 0.67, 95% CI 0.57 to 0.78, six trials with significant heterogeneity and continuous HR 0.53, 95% CI 0.43 to 0.65; two trials with no significant heterogeneity). The effect of continuous maintenance therapy on progression-free survival was not significantly different from switch therapy (interaction P=0.12). There was no evidence of statistically significant differences in overall survival and progression-free survival between switch maintenance therapy with cytotoxic agents and that with tyrosine kinase inhibitor agents.

Safety: Compared with observation or placebo, continuous maintenance therapy was associated with significantly greater rates of neutropenia (OR 14.6, 95% CI 2.6 to 82.4) and anaemia (OR 4.1, 95% CI 1.3 to 12.6), but not thrombocytopenia. Compared with observation or placebo, switch maintenance therapy was associated with significantly greater rates of alanine aminotransferase level (OR 6.4, 95% CI 1.2 to 35.1), diarrhoea (OR 5.8, 95% CI 1.3 to 25.4), rash (OR 13.4, 95% CI 2.0 to 89.0), fatigue (OR 8.4, 95% CI 1.9 to 37.2) and infection (OR 8.4, 95% CI 1.1 to 65.7). There was no evidence of significant differences between switch therapy and control in rates of neutropenia, anaemia, vomiting and anorexia, but the numbers of patients who experienced these adverse events were greater in the switch therapy group. No significant heterogeneity identified from Χ², but some adverse events had Ι² values greater than 25%.

There was no evidence of publication bias. Sensitivity analyses did not markedly change the estimates.

Authors' conclusions

Maintenance therapy with either switch or continuous strategies significantly increased overall and progression-free survival compared with observation or placebo, but was associated with increased toxicities.

CRD commentary

The review addressed a clear research question supported by appropriate inclusion criteria. A wide range of relevant sources were searched to identify studies and there were attempts to find unpublished studies, which minimised risks of ublication bias. There was no evidence of publication bias by formal testing, but there were too few studies for this finding to be reliable. The authors used appropriate methods to assess studies for quality and extract data, but they did not state how many reviewers selected studies for the review so reviewer error and bias from this process could not be ruled out. A valid tool was used for quality assessment and the included studies were generally of good quality; sensitivity analyses were undertaken to exclude one low quality study and the estimates did not change markedly. Synthesis of the studies and assessment of heterogeneity were both appropriate. Heterogeneity was explored with the use of subgroup analyses to take into account the different drugs used for maintenance. Substantial heterogeneity was identified for the pooled outcome of progression-free survival with switch maintenance therapy, but subgroup analysis suggested that this was partially explained by the different drugs used for therapy. The authors acknowledged that the interaction test to assess differences between estimates was likely to be underpowered because of small sample sizes. Adverse events were not well reported in the studies and many of the summary estimates for these outcomes had wide imprecise confidence intervals.

The review was well conducted. The authors' conclusions were based on generally high-quality studies and are likely to be reliable.

Implications of the review for practice and research

Practice: The authors stated that a drug chosen for maintenance therapy should have a favourable toxicity profile because of the long duration required and that the proper selection of initial therapy was critical for switch maintenance therapy. They stated that the findings of the review were applicable only to cytotoxic agents and tyrosine kinase inhibitors.

Research: The authors stated that concerns about increased toxicity meant that further research should evaluate patients' quality of life with maintenance therapy.

Funding

Ministry of Science and Technology of China.

Bibliographic details

Zhang X, Zang J, Xu J, Bai C, Qin Y, Liu K, Wu C, Wu M, He Q, Zhang S, Wei L, He J. Maintenance therapy with continuous or switch strategy in advanced non-small cell lung cancer: a systematic review and meta-analysis. Chest 2011; 140(1): 117-126. [PubMed: 21436247]

Indexing Status

Subject indexing assigned by NLM

MeSH

Carcinoma, Non-Small-Cell Lung /drug therapy /mortality; China /epidemiology; Disease-Free Survival; Humans; Lung Neoplasms /drug therapy /mortality; Practice Guidelines as Topic; Protein Kinase Inhibitors /therapeutic use; Survival Rate /trends; Treatment Outcome

AccessionNumber

12011005018

Database entry date

30/04/2012

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.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 21436247

PubMed Health Blog...

read all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...