Elsevier

Clinical Lung Cancer

Volume 13, Issue 4, July 2012, Pages 239-251
Clinical Lung Cancer

Review
Smoking History as a Predictive Factor of Treatment Response in Advanced Non–Small-Cell Lung Cancer: A Systematic Review

https://doi.org/10.1016/j.cllc.2011.08.003Get rights and content

Abstract

Recent trials in patients with advanced non–small-cell lung cancer (NSCLC) suggest that nonsmokers may benefit more from epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy than will smokers. The aim of this systematic review was to assess smoking history as a predictive factor for treatment outcomes in patients with NSCLC. Relevant published literature was identified through systematic searches of databases (MEDLINE, EMBASE, Cochrane Library), oncology and thoracic journals, and abstracts from major oncology conferences using prespecified criteria. Articles reporting treatment outcomes (overall survival [OS], progression-free survival [PFS], and/or response rate) in smoking history subgroups from randomized controlled trials of targeted therapy and/or chemotherapy were reviewed. Data from 30 trials (32 articles, 4 abstracts) were included. Of these, 23 trials tested first-line therapy. Treatment arms included EGFR TKIs (13 trials), EGFR monoclonal antibodies (2 trials), non-EGFR targeted treatments (9 trials), chemotherapy (27 trials), and placebo or best supportive care only (3 trials). Smoking history definitions and analyses of its effect on treatment outcomes varied widely. Only 11 trials reported testing for a treatment-by-smoking history interaction. The available evidence supports but does not confirm smoking history as a predictive factor for the response to TKIs, particularly in previously treated patients. The evidence does not support smoking history as a predictor of response to non–EGFR-targeted therapies or chemotherapy. Smoking history and its effect on treatment response are inadequately reported. More rigorous collection, analysis, and reporting may clarify whether smoking history is a predictor of treatment response in advanced NSCLC.

Introduction

Lung cancer is the leading cause of cancer-related death, both in the United States and globally.1, 2 Non–small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers and is commonly diagnosed at an advanced stage.3, 4 Regardless of therapy, the prognosis for advanced NSCLC is poor, with a median survival time of 6 to 12 months and a 1-year survival rate of 20%-30%.5, 6 To optimize survival outcomes for individual patients, oncologists seek clinical and molecular factors that can guide them toward the best choice of therapy.

Although the standard therapy for advanced NSCLC is a platinum-based combination of cytotoxic agents, non–platinum-based cytotoxic agents and targeted therapies have recently been introduced.7 Most notably, the epidermal growth factor receptor (EGFR) has been an important target for novel therapies, including the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib.3 Other targeted treatments, such as antiangiogenic therapies, have also been developed. Given the diverse molecular mechanisms underlying cancer, this variety of therapies may allow for individualized treatment provided that therapy can be appropriately and rationally selected.

There is increasing evidence that specific subpopulations of patients, identifiable by clinical or molecular characteristics, may derive greater benefit from certain anticancer therapies than from others. For example, pemetrexed is more effective in patients with nonsquamous tumors than in patients with squamous tumors.8 Similarly, tumors that harbor activating EGFR mutations are more responsive to EGFR TKIs than are tumors expressing wild-type EGFR, and EGFR mutations are much more prevalent in responders to TKIs than in nonresponders.9, 10, 11 Interestingly, EGFR mutations are more common among certain subpopulations of patients with NSCLC, such as women, patients of East Asian race, patients with adenocarcinoma histologic type, and never-smokers.12, 13 Accordingly there is evidence that these populations are more responsive to EGFR-targeted therapies.14, 15, 16, 17

Although most lung cancers occur in current or former smokers, approximately 10%-25% of patients with NSCLC worldwide are considered “never-smokers,” usually defined as having smoked fewer than 100 cigarettes in a lifetime.18, 19, 20 The proportion of never-smokers varies considerably among patient subgroups, with greater proportions in women compared with men and in Asian patients compared with white patients.2, 20 Indeed, more than 60% of Asian women with lung cancer are never-smokers.20 Sex and geographic variations in smoking habits may account for some of these differences.21 As smoking rates in some Western countries decline, the proportion of patients with NSCLC who are never-smokers is likely to rise in these countries.22 The cause of NSCLC in never-smokers is unknown, but environmental factors (eg, second-hand smoke or cooking fumes), genetic factors, and previous lung disease may all contribute.23

NSCLC in never-smokers differs from NSCLC in smokers in many respects.19, 20, 24, 25 For example, EGFR mutations appear to be more common in never-smokers than in smokers.26 Conversely, mutations in another cancer-related gene, KRAS, are more common in smokers than in never-smokers.20, 24, 27 Evidence suggests that these differences in molecular markers may have important implications for treatment choice.24, 27 There is also evidence that never-smokers generally survive longer than do smokers, regardless of treatment.28, 29, 30 Thus smoking history may be a prognostic factor for survival instead of or in addition to being predictive of response to specific treatments. Determining whether a clinical or molecular factor is prognostic or predictive requires prespecified statistical analyses with a treatment-by-factor interaction test used to identify predictive factors. Unfortunately data on smoking history and its relation to treatment response have been infrequently analyzed and reported and definitions of smoking history have varied considerably. Thus whether smoking history, along with other clinical and molecular factors, can be used to predict responsiveness to anticancer therapies and therefore inform physicians' choice of treatment, remains to be established.

The primary objective of this article-based systematic review was to assess smoking history as a predictive factor for treatment outcomes, particularly survival, in patients with advanced NSCLC. Specifically, the review focused on smoking history as a predictive factor for the response to systemic therapies, including chemotherapy and targeted therapies. The secondary objectives of this review were to assess how smoking history is recorded and defined in the literature and to assess the interaction of other patient characteristics, such as patient ethnicity, histologic tumor type, patient sex, and molecular markers, with smoking history in predicting treatment outcomes.

Section snippets

Database Search Strategy

The following databases were searched on September 2, 2010: MEDLINE through PubMed (from 1966), EMBASE (from 1975), and The Cochrane Library, including the Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials. Search terms from 4 categories were used: (1) NSCLC (including the medical subject heading [MeSH] carcinoma, non-small cell lung and the EMTREE term lung non–small-cell cancer), (2) advanced stage (including advanced, recurrent, metastatic, stage IIIB

Literature Search Results

A total of 483 article abstracts were retrieved by the combined database and journal searches (Figure 1). After removal of duplicates, 427 article abstracts were screened and 73 articles were selected for full text review. An additional 7 articles (cited by reviews or key research articles) were also included in the full text review. Four conference abstracts met the inclusion criteria. Of the articles reviewed, 48 did not meet the inclusion criteria, primarily because smoking history subgroup

Discussion

Clinical and molecular factors that are predictive of treatment response are valuable when deciding on the best treatment strategy for individual patients. Although EGFR mutation is an example of a predictive factor in NSCLC, the mutation status of patients cannot always be assessed in the clinical setting, especially in previously treated patients. Additional predictive factors would be useful, not only for treating patients with unknown EGFR status but also for treating those with wild-type

Conclusions

The results of this systematic review suggest but do not confirm that smoking history may be a useful predictor for responsiveness to treatment for advanced NSCLC. In the clinic physicians should consider the smoking history of patients in conjunction with other possible predictive factors, response to previous therapy, and patient preferences when choosing treatment strategies. Future trials in which smoking-related data are collected, analyzed, and reported should provide a clearer picture of

Disclosure

Paul Mitchell has received honoraria from Eli Lilly and Roche and has been a member of advisory boards for Astra Zeneca, Eli Lilly, Pfizer, Boehringer Ingelheim, Roche, Merck Serono, and Specialised Therapeutics. He has also received travel assistance and accommodation from Merck Serono and provided testimony for Merck Serono. Tony Mok has received honoraria from Astra Zeneca, BMS, Eli Lilly, Pfizer, and Roche and has been a consultant to Astra Zeneca, Eli Lilly, Esai Pharmaceuticals, Pfizer

Acknowledgments

The authors would like to thank Luke Carey, PhD, (ProScribe Medical Communications) for his assistance with the literature review and Susanna Holt, PhD, (Eli Lilly and Company) for her editorial and administrative assistance.

This systematic review was sponsored by Eli Lilly and Company. In compliance with the Uniform Requirements for Manuscripts, established by the International Committee of Medical Journal Editors, Eli Lilly and Company did not impose any impediment, directly or indirectly, on

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      However, none of these studies compared the PFS and ORR on EGFR-TKI therapy in patients with EGFR mutations according to cigarette smoking history and dosage. Recently, a meta-analysis conducted by Mitchell et al. also concluded that cigarette smoking and its effect on EGFR-TKI response has still not been determined, because data on smoking history and its relationship with treatment response have been incomprehensively analyzed [13]. Our study has particular value in that it includes a sufficient follow-up period as part of a comprehensive analysis of cigarette smoking history and survival outcome.

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