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Chemo-radiotherapy for advanced non-small cell lung cancer: concurrent or sequential? It's no longer the question: a systematic review

HY Liang, H Zhou, XA Li, ZH Yin, P Guan, and BS Zhou.

Review published: 2010.

Link to full article: [Journal publisher]

CRD summary

The authors concluded that concurrent radio-chemotherapy exhibited superiority over sequential radiotherapy-chemotherapy in the treatment of advanced non-small-cell-lung-cancer. The conclusions are likely to be reliable, although a number of weaknesses (likelihood of error and bias in study selection and quality assessment and potential publication and language biases) suggest a need for some caution.

Authors' objectives

To compare the effect of concurrent and sequential radiotherapy-chemotherapy on overall survival, response rate, failure patterns and toxicity in patients with advanced non-small-cell-lung-cancer (NSCLC).

Searching

PubMed, Proceedings of American Society of Clinical Oncology and Proceedings of European Society of Medical Oncology were searched for published and unpublished trials that had completed patient enrolment by 31 August 2009. Search terms were reported. Reference lists of original articles, review articles and relevant books were handsearched. Only articles published in English were considered.

Study selection

Randomised controlled trials (RCTs) that compared concurrent to sequential radiotherapy-chemotherapy in the management of treatment-naive patients with pathologically confirmed advanced NSCLC were eligible for inclusion. Interventions that added systematic dose sequential chemotherapy to a concurrent arm (as either induction or consolidation strategy) were considered. Studies designed to detect cost differences or that included insufficient outcomes or non-operable patients were excluded. The primary outcome measure was overall survival. Secondary outcome measures included progression-free survival, objective response rate, failure patterns and toxic events.

All included studies (except one conducted in India) were in developed countries. Median study follow-up time was 3.3 years (range 1.3 to 6.0 years). Study eligibility criteria (age, performance status, weight loss, disease stage and previous treatment) were varied. Included studies evaluated different radiotherapy and chemotherapy regimens (drugs, doses, types of radiotherapy) and treatment schedules. Conformal radiotherapy was used as the primary type. Cisplatin-based chemotherapy regimens investigated included vindesine, mitomycin, vinorelbine, etoposide, docetaxel, gemcitabine, vinblastine and ifosfamide. Carboplatin-based chemotherapy consisted of paclitaxel alone.

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

Assessment of study quality

Methodological quality was assessed using a checklist based on the Method for Evaluating Research and Guideline Evidence criteria reported by Liddle et al. Key criteria assessed included randomisation, blinding, outcome measures, measure assessment, arm comparability and loss to follow-up. Each study was assigned an overall score of A (low risk of bias), B1 (low to moderate risk of bias), B2 (moderate to high risk of bias) and C (high risk of bias).

The authors did not state how many reviewers assessed study quality.

Data extraction

Two reviewers independently abstracted data required to calculate median ratios and progression-free-survival ratios (for median survival and progression-free survival) and odds ratios (ORs) (for objective response rate, relapse control rate and toxic events), and their corresponding 95% confidence intervals (CIs).

Trial authors were contacted for additional information. Disagreements were resolved by discussion.

Methods of synthesis

Pooled median ratios and progression-free-survival ratios for median survival and progression-free survival, and their corresponding 95% CIs, were calculated using the weighted sum of the log ratio of the median ratio and progression-free-survival ratio of individual studies. Stouffer's method was used to pool p-values for survival. Pooled odds ratios and their corresponding 95% CIs were calculated using the Mantel-Haenszel method where there was no evidence of heterogeneity; otherwise a random-effects model was used.

Statistical heterogeneity was assessed using the Cochran Q test and I2 statistic. Sensitivity analysis was done by excluding all phase II trials not designed to assess effects on overall survival. Publication bias was assessed using a funnel plot and Begg and Mazumdar and Egger tests.

Results of the review

Eleven RCTs were included (n=2,043, concurrent n=1,019 and sequential n=1,024): six RCTs were phase III trials and five RCTs were phase II trials. The overall quality score was rated as B1 (low to moderate risk of bias) for all included studies except one study rated C (high risk of bias).

Overall survival: Concurrent compared with sequential radiotherapy-chemotherapy was associated with a significantly higher median overall survival (median ratio 1.17, 95% CI 1.09 to 1.26; n=1,939, 10 RCTs).

Progression-free survival: Concurrent radiotherapy-chemotherapy showed no clear advantage over sequential with regard to progression-free survival (progression-free-survival ratio 1.04, 95% CI 0.93 to 1.16; n=1,559, nine RCTs). A trend in favour of the concurrent arm was noted (median progression-free survival concurrent 9.8 months versus sequential 9.1 months).

Patterns of failure: Concurrent radiotherapy-chemotherapy compared with sequential was associated with significantly lower odds of overall tumour relapses (locoregional or distant) (OR 0.82, 95% CI 0.69 to 0.97, I2=0%). No evidence of publication bias was found.

Response rate: Concurrent radiotherapy-chemotherapy compared with sequential was associated with significantly higher objective response rate (random-effects OR 1.38, 95% CI 1.10 to 1.72, Cochran Q p-value=0.007, I2=62.0%; n=1,352, nine RCTs). No evidence of publication bias was found.

Toxicity: Grade III or more neutropenia was significantly more frequent with the concurrent arm (OR 2.30, 95% CI 1.71 to 3.10), as were thrombocytopenia (OR 2.41, 95% CI 1.72 to 3.40), nausea/vomiting (OR 1.49, 95% CI 1.08 to 2.06), stomatitis (OR 2.84, 95% CI 1.01 to 8.00) and esophagitis (OR 4.88, 95% CI 3.37 to 7.30). Grade III or greater anaemia was significantly more frequent with sequential arm (OR 0.12, 95% CI 0.09 to 0.15).

There was no significant difference in the number of treatment-related severe pulmonary, neurological, infection, cardiovascular, liver and renal toxicity between the two strategies.

Authors' conclusions

Concurrent radiotherapy-chemotherapy exhibited superiority over sequential radiotherapy-chemotherapy in the treatment of advanced NSCLC. Further improvements may be obtained by optimising the conditions for the concurrent regimen.

CRD commentary

The review question was clearly stated. As only one database was searched and non-English papers were excluded, relevant papers may have been missed. Steps were taken to minimise risk of reviewer error and bias in data extraction; it was unclear whether similar steps were taken in study selection and validity assessment. Study quality was assessed with appropriate criteria and results were reported to be of low to moderate risk of bias. Appropriate statistical methods were used to assess statistical heterogeneity and combine study results. The authors acknowledged the possibilities of publication bias and statistical heterogeneity.

The authors' conclusions are likely to be reliable, although a number of weaknesses (likelihood of error and bias in study selection and quality assessment and potential publication and language biases) suggest a need for some caution.

Implications of the review for practice and research

Practice: The authors stated that the findings confirmed the beneficial effect of concurrent chemotherapy in advanced NSCLC and supported its use in routine clinical practice.

Research: The authors stated that further systematic reviews that used individual patient data should be conducted to compare the efficacy of concurrent radiotherapy-chemotherapy with sequential arm.

Funding

Liaoning Provincial Department of Education (2008S232); China Medical Board (00726).

Bibliographic details

Liang HY, Zhou H, Li XA, Yin ZH, Guan P, Zhou BS. Chemo-radiotherapy for advanced non-small cell lung cancer: concurrent or sequential? It's no longer the question: a systematic review International Journal of Cancer 2010; 127(3): 718-728. [PubMed: 19957329]

Indexing Status

Subject indexing assigned by NLM

MeSH

Antineoplastic Combined Chemotherapy Protocols /adverse effects; Carcinoma, Non-Small-Cell Lung /drug therapy /radiotherapy; Combined Modality Therapy; Humans; Lung Neoplasms /drug therapy /radiotherapy; Survival Analysis

AccessionNumber

12010005391

Database entry date

23/03/2011

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.

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

Copyright © 2014 University of York.

PMID: 19957329

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