Abstract C49: A randomized phase II trial of low-dose aspirin versus placebo in high-risk individuals with CT screen-detected subsolid lung nodules

Lung cancer screening by spiral low-dose CT scan (ld-CT) is a noninvasive test with low radiation exposure and no contrast medium and offers the opportunity to serially examine the peripheral lung for the first time, albeit with the limitation that small lesions cannot be biopsied, leaving their identity unknown. However, the incidence of undetermined nodules detected with ld-CT is more than 50% in high-risk individuals. The nature of these nodules remains uncertain but some of them could represent precancerous lesions. Particularly, ground glass opacities (GGO), compared with solid nodules, can represent localized bronchioloalveolar carcinoma without foci of active fibroblastic proliferation or atypical adenomatous hyperplasia, a putative adenocarcinoma precursor lesion. Two screening programs with annual ld-CT in current and former smokers are run at the EIO and they may represent suitable cohorts of at-risk subjects to be enrolled in a chemopreventive study. Aspirin, the first nonsteroidal anti-inflammatory drug (NSAID) identified, may have anti-cancer properties, especially for diseases whose etiology implicates chronic inflammation including lung cancer. The anti-inflammatory effect of NSAIDs operates through inhibition of prostaglandins via suppression of cyclooxygenase-1 (COX-1) and COX-2. Evidence of this effect is derived from several recently published meta-analyses of aspirin in the prevention of cardiovascular events showing that daily aspirin reduced the incidence of several cancers and reduced metastases. In 2011, Rothwell et al. pooled data from 8 double-blind randomized controlled trials of daily aspirin and analyzed the effect of aspirin on cancer mortality as secondary endpoints. The 20-year risk of death due to all cancers was lower in the aspirin than in the control group and the benefit increased with treatment duration. Lung cancer-specific mortality rates were reduced by 29% (95% CI, 11-42) in the aspirin group in the 20-year period after the trial commenced. No trend with dose (above 75 mg/day) was observed, but the effect on all cancers was more evident in adenocarcinomas and was present in both smokers and nonsmokers. Several further observational studies have been published confirming a lower lung cancer risk in aspirin users. Based on the growing evidence on the potential preventive effect of Aspirin on lung cancer, we will conduct a monoinstitutional, double-blind, placebo-controlled phase IIb study in which 128 participants enrolled in a ld-CT annual screening program will be randomized to receive either low dose Aspirin (100 mg/day) or placebo for 12 month. The primary endpoint will be the shrinkage of GGO and partially solid nodules after one-year treatment in a per-lesion and per-subject analysis. Secondary endpoints will be the modulation of biological markers and their potential correlation with modification of lung nodules shrinkage. In particular, we will evaluate the effect of Aspirin on a signature of serum miRNA correlated to subsolid nodules. Other secondary endpoints will be the evaluation of lung nodule density before and after treatment and the number and size of non-target lesions. Additional circulating biomarkers will include the modulation of hs-CRP as a marker of inflammation, the evaluation of urinary cotinine as marker of tobacco exposure and investigation of the potential effect of aspirin according to its concentration, the measurement of urinary prostaglandin metabolites (PGEM) and urine LTE4. Tolerability of low dose Aspirin will be also evaluated. The study is expected to start by December 2013. Supported by NCI, DCP Contract HHSN261201200034I to the UT MD Anderson Cancer Prevention Agent Development Program: Early Phase Clinical Research Citation Format: Aliana Guerrieri-Gonzaga, Giulia Veronesi, Pier Paolo Di Fiore, Matteo Lazzeroni, Massimo Bellomi, Eva Szabo, Lana A. Vornik, Powel H. Brown, Bernardo Bonanni. A randomized phase II trial of low-dose aspirin versus placebo in high-risk individuals with CT screen-detected subsolid lung nodules. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr C49.