Assessing Efficacy in Early-Phase Cancer Prevention Clinical Trials: The Case of Ki-67 in the Lung

Szabó, Éva

doi:10.1158/1940-6207.capr-09-0268

Cited by 6 publications

(8 citation statements)

References 23 publications

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“…Validated SEBs, probably in combinations, for early-phase trials that could amplify the progress of lung cancer chemoprevention are a messy problem beyond the scope of this discussion (40). Nevertheless, our collective biomarker data provide strong evidence for the potential efficacy of celecoxib for lung cancer prevention, particularly in former smokers.…”

Section: Discussionmentioning

confidence: 99%

Lung Cancer Chemoprevention with Celecoxib in Former Smokers

Mao

Roth

Fishbein

et al. 2011

Cancer Prevention Research

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Ample studies suggest that the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway plays a pivotal role in carcinogenesis and that COX-2 inhibition may help prevent lung cancer. Therefore, we conducted a randomized, double-blind, placebo-controlled trial of the COX-2 selective inhibitor celecoxib (400 mg bid for 6 months) in former-smokers (age ≥45, ≥30 pack-years of smoking, ≥1 year of sustained abstinence from smoking). We assessed the impact of celecoxib on cellular and molecular events associated with lung cancer pathogenesis; the primary endpoint was bronchial Ki-67 labeling index (Ki-67 LI). Of 137 randomized subjects, 101 completed both baseline and 6-month bronchoscopies and were evaluable for the primary endpoint analysis. The beneficial effect on Ki-67 LI was greater in the celecoxib arm (versus placebo) in a mixed-effects analysis (P = 0.0006), and celecoxib significantly decreased Ki-67 LI by an average of 34%, whereas placebo increased Ki-67 LI by an average of 3.8% (P = 0.04; t-test). Participants crossed over to the other study arm at 6 months. Therefore, at 12 months all remaining participants had received 6 months of celecoxib, and their decreases in Ki-67 LI correlated with a reduction and/or resolution of lung nodules on computed tomography. Celecoxib significantly reduced plasma c-reactive protein and interleukin-6 mRNA and protein and increased 15(S)-hydroxy-eicosatetraenoic acid levels in BAL samples. The baseline ratio of COX-2 to 15-hydroxyprostaglandin dehydrogenase mRNA in bronchoalveolar lavage (BAL) cells was a significant predictive marker of Ki-67 response to celecoxib (P = 0.002). Our collective findings support the continued investigation of celecoxib for lung cancer chemoprevention in former smokers at a low risk of cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

Lung Cancer Chemoprevention with Celecoxib in Former Smokers

Mao

Roth

Fishbein

et al. 2011

Cancer Prevention Research

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“…These findings, although not previously described in the recently reported trials of celecoxib or iloprost, 10,30 may be due to outside events, which can influence rates of Ki-67. 30,31 Furthermore, Ki-67 may not be sufficiently specific and sensitive for predicting future lung cancer development by itself. 31,32 …”

Section: Discussionmentioning

confidence: 99%

Phase 2 randomized study of enzastaurin (LY317615) for lung cancer prevention in former smokers

Gray

Altiok

Alexandrow

et al. 2012

Cancer

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BACKGROUND Chemoprevention for lung cancer with neutraceuticals or anti-inflammatory agents has had mixed clinical benefit. Novel targeted agents hold the promise of greater efficacy and selectivity. Here, we evaluated enzastaurin, a selective PKC-β inhibitor with antiproliferative and proapoptotic properties in former smokers. METHODS The primary objective was to compare the average fraction of Ki-67 stained cells (labeling index [LI]) in bronchial biopsies collected before and after treatment. Subjects were randomized (2:1) to 6 months of daily oral enzastaurin (500mg) or placebo. Stratification was based on morphology, history of lung cancer, and airway obstruction. RESULTS In pretrial investigations, we established the rationale for PKC-β inhibition and pathway interrogation in premalignant lesions and early stage lung cancer. In the intent-to-treat analysis, of 40 subjects randomized, there was no significant difference in the pre/post-treatment change of the Ki-67 LI between the enzastaurin and placebo groups (p = 0.53). Six subjects discontinued enzastaurin (n=4, AEs: abdominal distension, DVT, hyponatremia, and rash; n=2, subject decision) and one placebo (noncompliance). Two subjects had ≥1 serious AEs (bradycardia, DVT, and hypotension). CONCLUSIONS This represents the first chemoprevention trial with a non-FDA-approved, oral, small-molecule targeted agent. Although the primary endpoint was not met, enzastaurin was found to be tolerable for 6 months by 75% of subjects with a suggestion of response in a subset analysis restricted to metaplastic or dysplastic lesions.

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“…Celecoxib had no significant effect on any of three measures of histopathology outcome [average and maximum World Health Organization (WHO) score and dysplasia index], although there was a trend favoring celecoxib in maximum histopathology score. Although Ki-67 is nonspecific and can be reduced in low-risk people without regard to carcinogenesis (28), its believability in this study stems from findings of substantial, significant reductions in Ki-67 versus placebo and, more important, of supportive changes in several specific molecular markers of inflammation and carcinogenesis. For example, celecoxib also reduced IL-6 gene (in BAL cells) or protein (in BAL fluid) expression, which is a key inflammatory mediator of lung carcinogenesis (29).…”

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confidence: 88%

The Dawn of a Revolution in Personalized Lung Cancer Prevention

Khuri

2011

Cancer Prevention Research

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Lung cancer prevention and early detection, which have fallen on hard times for more than the past 20 years, seem to have turned a corner toward better times ahead. Exciting new results of randomized controlled trials that targeted the arachidonic acid pathway, including a celecoxib trial reported by Mao and colleagues in this issue of the journal (beginning on page 984) and a trial of the prostacyclin analog iloprost, complement recently reported 20%-30% lung cancer mortality reductions, either with aspirin in targeting the arachidonic acid pathway or with computed tomography screening. The new results show encouraging activity personalized to former smokers and/or people expressing predictive biomarkers. These trials and technological advances in molecular profiling and imaging herald substantial clinical advances on the horizon of this field. Cancer Prev Res; 4(7); 949-53. '2011 AACR."It was the best of times, it was the worst of times. . .it was the spring of hope, it was the winter of despair" -Charles Dickens (A Tale of Two Cities)The well-known litany of disappointments in clinical lungcancer prevention includes the Alpha-Tocopherol, BetaCarotene (ATBC) trial, Carotene and Retinol Efficacy Trial (CARET), Lung Intergroup Trial (LIT), and the finding that, important as smoking cessation is, half of all new lung cancers arise in former smokers (1-5). Furthermore, a very recent randomized controlled trial (RCT) of selenium to prevent new cancer in resected early-stage lung-cancer patients reported negative outcomes (6). The worst of times. For people living with an increased risk of lung cancer, however, the glass is starting to look somewhat fuller. Reversing decades of disappointing results of lung cancer early detection research with chest-X-ray screening (7), the definitive randomized controlled National Lung Screening Trial (NLST) showed that screening high-risk current or former smokers with computed tomography (CT) scans reduced lung-cancer mortality by 20%, a remarkable but far from bloodless success (8). CT scanning became the most contentious debate of the lung cancer field-one side asserting that it should be implemented without delay on the heels of strong early data (including those of Henschke and colleagues; ref. 9) for reducing lungcancer mortality, the other side asserting that it should be implemented only after a definitive RCT has confirmed benefit (8). Success has many "fathers," and both camps claimed affirmation, even vindication, by the NLST results. Meanwhile, and more subtly, analyses of RCTs of daily aspirin to reduce the risk of vascular disease found a 30% reduction in lung-cancer mortality in people taking daily aspirin for five or more years (10). The early-2011 report of this clinical targeting of the arachidonic acid pathway is prelude to three trials reported in the past year showing that targeting the same pathway with different agents is effective in reversing proliferation or histologic changes in the lungs of former smokers (11-13).These three trials effectively t...

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Assessing Efficacy in Early-Phase Cancer Prevention Clinical Trials: The Case of Ki-67 in the Lung

Cited by 6 publications

References 23 publications

Lung Cancer Chemoprevention with Celecoxib in Former Smokers

Lung Cancer Chemoprevention with Celecoxib in Former Smokers

Phase 2 randomized study of enzastaurin (LY317615) for lung cancer prevention in former smokers

The Dawn of a Revolution in Personalized Lung Cancer Prevention

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