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Management Brief No. 63

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Management eBriefs
Issue 63March 2013

A Systematic Review of Comparative Effectiveness and Cost-Effectiveness: Treatment of Metastatic Non-Small Cell Lung Cancer

Most patients with lung cancer are diagnosed when the cancer is already advanced (stage III or IV), and surgery is no longer a viable option. Small cell lung cancer and non-small cell lung cancer (NSCLC) are treated as different diseases in terms of therapy. This review was requested to evaluate the current evidence on the effectiveness and cost-effectiveness of treatments for advanced NSCLC. Investigators with the VA Evidence-based Synthesis Program at the West Los Angeles VA Medical Center conducted a review of the literature from 1/1/1966 through 3/16/2012. After reviewing more than 1,500 articles and trials, 55 articles and 60 trial citations were determined to be appropriate for addressing the following four key questions regarding patients with NSCLC.

Question #1
What is the comparative effectiveness of the different recommended (e.g. consistent with National Comprehensive Cancer Network (NCCN) guidelines) first-line chemotherapy regimens? Findings show:

Of the 55 articles used in this review, 24 were relevant to this question. Of the 60 trial citations, 43 were relevant. Findings suggest:

  • New trials continue to support the conclusion of previous systematic reviews that any differences in survival between platinum-based doublets are modest.
  • Doublet chemotherapy (e.g. two-drug chemotherapy) including a platinum agent, probably has a slight advantage over doublets that don't include platinum agents. Doublet chemotherapy probably has a slight benefit in terms of survival compared to singlet therapy, but causes more toxicity.
  • Cisplatin doublets may have a slight advantage over carboplatin combinations in terms of survival and response rate. However, carboplatin generally has a milder toxicity than cisplatin.
  • In general, erlotinib or gefitinib monotherapy is superior in terms of progression-free survival and adverse events than cytotoxic chemotherapy in patients with epidermal growth factor receptor (EGFR) mutations.

Question #2
What is the comparative effectiveness of the different recommended (e.g. NCCN,) second-line chemotherapy regimens? Findings show:

  • Considering data from first-line and maintenance therapy studies in addition to second-line studies, there are sufficient data to support the conclusion that histology type influences the effectiveness of potential treatments. Pemetrexed is more effective in NSCLC histologies, other than squamous cell carcinoma, than it is in squamous cell carcinoma.
  • The tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib, when used as second-line therapy in patients unselected for EGFR mutation status, produce overall survival similar to docetaxel. This is probably due to a mix of EGFR wild-type and mutation-positive patients in the population, with TKIs effective only for the latter.
  • Doublet second-line cytotoxic therapy might offer slight benefits in progression-free survival and response rate compared to single drug chemotherapy, but at a cost of increased toxicity.
  • There is insufficient data to support effectiveness of drugs other than docetaxel, pemetrexed, and erlotinib in second-line therapy.
  • The above second-line studies are typically undertaken after evidence of disease progression, and should be distinguished from maintenance therapy, which is undertaken when a patient has at least stable disease during treatment (typically four cycles).

Question #3
What is the benefit of maintenance therapy following first-line chemotherapy regimens compared with no maintenance therapy? Findings show:

  • Study design issues limit the ability to make strong conclusions about maintenance therapy and survival.
  • There is insufficient evidence to reach conclusions regarding whether a continuous or a switch strategy is superior. However, two drugs have been approved for switch therapy.
  • Patients with EGFR mutations should be treated with tyrosine kinase inhibitors (erlotinib, gefitinib).

Question #4
What is the relative cost and cost-effectiveness of the different approaches in Key Questions 1-3? Findings show:

  • There are a large number of published cost-effectiveness analyses, but approximately two-thirds of such studies are supported by the makers of the drugs being assessed.
  • Studies supported by the makers concluded that their drug was cost-effective. Of the cost-effectiveness analyses not supported by the industry, the addition of bevacizumab to first-line therapy was found in one study not to be cost-effective, erlotinib was found in one study to be marginally cost-effective, while the differences between erlotinib and docetaxel maintenance therapy were slight in another study.

Future Research
Since VA policymakers are greatly interested in cost effectiveness in the VA healthcare system, a proper cost-effectiveness analysis — using VA data and adjusting the population characteristics for VA patient characteristics — is needed to reach strong conclusions about the cost effectiveness of these drugs in the VA setting. Such a study should be possible by combining data from this review on effectiveness with data from VA databases on the number of Veterans being treated, how they are being treated, the resources used, and their outcomes. Sensitivity analysis can be used to estimate the degree to which baseline assumptions would need to change in order to reach different concusions about cost-effectiveness.

A Cyberseminar session on this ESP Report was held on January 15, 2013. To access the archived session, please go to the VA INTRANET HSR&D Cyberseminar web page (intranet only):

This report is a product of VA/HSR&D's Quality Enhancement Research Initiative's (QUERI) Evidence-Based Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers — and to disseminate these reports throughout VA.


Maher, AR, Miake-Lye, IM, Beroes, JM, Shekelle, PG. Treatment of Metastatic Non-Small Cell Lung Cancer: A Systematic Review of Comparative Effectiveness and Cost Effectiveness. VA-ESP Project #05-226; 2012.

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This Management eBrief is a product of the HSR&D Evidence Synthesis Program (ESP). ESP is currently soliciting review topics from the broader VA community. Nominations will be accepted electronically using the online Topic Submission Form. If your topic is selected for a synthesis, you will be contacted by an ESP Center to refine the questions and determine a timeline for the report.

This Management e-Brief is provided to inform you about recent HSR&D findings that may be of interest. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs. If you have any questions or comments about this Brief, please email CIDER. The Center for Information Dissemination and Education Resources (CIDER) is a VA HSR&D Resource Center charged with disseminating important HSR&D findings and information to policy makers, managers, clinicians, and researchers working to improve the health and care of Veterans.

This report is a product of the HSR&D Evidence-Based Synthesis Program (ESP), which was established to provide timely and accurate synthesis of targeted healthcare topics of particular importance to VA managers and policymakers - and to disseminate these reports throughout VA.

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