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Chest

Volume 143, Issue 5, Supplement, May 2013, Pages e40S-e60S
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Chemoprevention of Lung Cancer: Diagnosis and Management of Lung Cancer, 3rd ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

https://doi.org/10.1378/chest.12-2348Get rights and content

Background

Lung cancer is the most common cause of cancer death in men and women in the United States. Cigarette smoking is the main risk factor. Former smokers are at a substantially increased risk of developing lung cancer compared with lifetime never smokers. Chemoprevention refers to the use of specific agents to reverse, suppress, or prevent the process of carcinogenesis. This article reviews the major agents that have been studied for chemoprevention.

Methods

Articles of primary, secondary, and tertiary prevention trials were reviewed and summarized to obtain recommendations.

Results

None of the phase 3 trials with the agents β-carotene, retinol, 13-cis-retinoic acid, α-tocopherol, N-acetylcysteine, acetylsalicylic acid, or selenium has demonstrated beneficial and reproducible results. To facilitate the evaluation of promising agents and to lessen the need for a large sample size, extensive time commitment, and expense, surrogate end point biomarker trials are being conducted to assist in identifying the most promising agents for later-stage chemoprevention trials. With the understanding of important cellular signaling pathways and the expansion of potentially important targets, agents (many of which target inflammation and the arachidonic acid pathway) are being developed and tested which may prevent or reverse lung carcinogenesis.

Conclusions

By integrating biologic knowledge, additional early-phase trials can be performed in a reasonable time frame. The future of lung cancer chemoprevention should entail the evaluation of single agents or combinations that target various pathways while working toward identification and validation of intermediate end points.

Section snippets

Summary of Recommendations

3.1.1.1. For individuals with a greater than 20 pack year history of smoking or with a history of lung cancer, the use of β carotene supplementation is not recommended for primary, secondary, or tertiary chemoprevention of lung cancer (Grade 1A).

Remarks: The dose of β carotene used in these studies was 20-30 mg per day or 50 mg every other day.

3.5.1.1. For individuals at risk for lung cancer and for patients with a history of lung cancer, the use of vitamin E, retinoids, and N-acetylcysteine

Methods

In 2011-2012, a panel of experts corresponded to update the previous recommendations for the chemoprevention of lung cancer. The panel consisted of investigators experienced in the formulation, design, and execution of chemoprevention clinical trials. Disagreements were resolved to establish guidelines for practitioners to use for patients at high risk of developing lung cancer.

To come to a consensus on the various lung cancer chemoprevention guidelines presented in this topic, a systematic

Identification of Candidate Agents

The selection of appropriate targets for chemopreventive interventions requires a careful risk-benefit analysis that balances efficacy with potential harms related to the intervention. Indications of effectiveness are derived from knowledge of mechanisms, preclinical (in vitro and in vivo) experimental data, epidemiologic studies, and existing data from clinical trials, either early-phase cancer prevention trials or secondary analyses from trials performed for other indications.31 Ongoing

β-Carotene: Use in Former and Current Smokers and Those With Asbestos Exposure

Based on epidemiologic data, a diet rich in fruits and vegetables (at least three servings per day) is associated with a lower cancer incidence. The α-Tocopherol β-Carotene (ATBC) study randomized 29,133 people to receive α-tocopherol, β-carotene, both, or placebo.65 Study participants were followed for 5 to 8 years. The incidence of lung cancer in the study group was 18% higher than in the placebo group (P < .01). A second trial evaluating β-carotene, the β-Carotene and Retinol Efficacy Trial

Intermediate End Point Biomarkers in Chemoprevention Clinical Trials

Randomized controlled phase 3 clinical trials represent the definitive way to demonstrate preventive efficacy by assessing the ability of an intervention to affect cancer incidence and mortality. Phase 2 efficacy cancer prevention trials, on the other hand, rely on short-term (or intermediate) end points that are theoretically predictive of patient outcomes such as cancer incidence. In contrast to phase 3 cancer treatment trials that rely on tumor measurements to assess agent efficacy, phase 2

Arachidonic Pathway and Lung Cancer Chemoprevention

Arachidonic acid is metabolized to prostaglandins and prostacyclin (PGI2) by the COX pathway, whereas leukotrienes are formed via the lipoxygenase (LOX) pathway. Their end products have been closely linked to carcinogenesis.102 Two isoforms of COX exist: COX-1 and COX-2. COX-1 exists in most cells and is constitutively active. In contrast, COX-2 is induced by inflammatory and mitogenic stimuli that lead to increased prostaglandin formation in inflamed and neoplastic tissues.102 Despite having

Myo-inositol

Myo-inositol is found in a wide variety of foods, such as whole grains, seeds, and fruits. It is a source of several second messengers, including diacylglycerol, and is an essential nutrient required by human cells for growth and survival in culture. Multiple animal studies show that myo-inositol inhibits carcinogenesis by 40% to 50% in both the induction and postinitiation phase.137, 138 In combination with budesonide, its efficacy is up to 80%.131 Mechanistically, the PI3K pathway that is

Other Potential Targeted Agents for Development

Many other targeted therapeutic agents exist with potential as chemopreventive agents. Some potential targets for lung chemoprevention, are:

  • •

    cyclooxygenase

  • •

    prostacyclin

  • •

    histone deacetylase

  • •

    insulin growth factor 1 receptor

  • •

    mammalian target of rapamycin

  • •

    epidermal growth factor receptor

  • •

    protein kinase C

  • •

    signal transducer and activator of transcription 3

  • •

    5-, 12-lipoxygenase

  • •

    vascular endothelial growth factor

Selected targets are discussed here.

Conclusions/Future Directions

Lung cancer chemoprevention is a developing area of research whose main goal is to find an effective agent with a favorable toxicity profile for subjects at a high risk of developing a primary or secondary lung cancer. Lung cancer is no longer viewed as a single disease broken down into histologic categories; instead, genotyping of tumors to identify targetable molecular abnormalities for which there are approved therapies (eg, erlotinib for EGFR mutations and crizotinib for echinoderm

Acknowledgments

Author contributions: Dr Keith had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Szabo: contributed to the conception and design; collection and assembly of data; data analysis and interpretation; manuscript writing, review, and revision; and final approval.

Dr Mao: contributed to the conception and design; collection and assembly of data; data analysis and interpretation; manuscript writing, review,

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    COI Grids reflecting the conflicts of interest that were current as of the date of the conference and voting are posted in the online supplementary materials.

    Disclaimer: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://dx.doi.org/10.1378/chest.1435S1.

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

    Funding/Sponsors: The overall process for the development of these guidelines, including matters pertaining to funding and conflicts of interest, are described in the methodology article. The development of this guideline was supported primarily by the American College of Chest Physicians. The lung cancer guidelines conference was supported in part by a grant from the Lung Cancer Research Foundation. The publication and dissemination of the guidelines was supported in part by a 2009 independent educational grant from Boehringer Ingelheim Pharmaceuticals, Inc.

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