A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia.
BACKGROUND
Results from preclinical studies have suggested that the organosulfur compound anethole dithiolethione (ADT) may be an effective chemopreventive agent for lung cancer. We conducted a phase IIb study to determine the effects of ADT in smokers with bronchial dysplasia.


METHODS
One hundred twelve current and former smokers with a smoking history of at least 30 pack-years and at least one site of bronchial dysplasia identified by an autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive placebo or ADT at 25 mg orally thrice daily for 6 months. Each subject then underwent a follow-up bronchoscopy-directed biopsy. We used changes in histopathologic grade and nuclear morphometry index (MI) as the primary and secondary end point biomarkers, respectively. Chi-square tests with continuity correction were used to compare response rates on a lesion- and person-specific basis between the two study groups. All statistical tests were two-sided.


RESULTS
One hundred one subjects had a follow-up bronchoscopy. In the lesion-specific analysis, progression rate of pre-existing dysplastic lesions by two or more grades and/or the appearance of new lesions was statistically significantly lower in the ADT group (8%) than in the placebo group (17%) (P<.001; difference = 9%, 95% confidence interval [CI] = 4% to 15%). In the person-specific analysis, the disease progression rate was statistically significantly lower in the ADT group (32%) than in the placebo group (59%) (P =.013; difference = 27%, 95% CI = 6% to 48%). The two treatment groups did not differ statistically significantly in terms of nuclear MI. Among individuals with an abnormal nuclear MI before treatment (29 in the ADT group and 25 in the placebo group), the progression rate in the ADT group (41%) was substantially lower than that in the placebo group (60%), although the difference was not statistically significant (P =.28; difference = 19%, 95% CI = -11% to 49%). Adverse events were mostly minor gastrointestinal symptoms that resolved with dose reduction or discontinuation of the medication.


CONCLUSIONS
Our results suggest that, in smokers, ADT is a potentially efficacious chemoprevention agent for lung cancer.
Lam
Stephen
S
Department of Respiratory Medicine, British Columbia Cancer Agency and the University of British Columbia, Vancouver, Canada. sclam@interchange.ubc.ca
MacAulay
Calum
C
Le Riche
Jean C
JC
Dyachkova
Yulia
Y
Coldman
Andy
A
Guillaud
Martial
M
Hawk
Ernest
E
Christen
Marie-Odile
MO
Gazdar
Adi F
AF
D000328:Adult; D000368:Aged; D000781:Anethole Trithione / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001980:Bronchi / Q000473:pathology*; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000473:pathology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008679:Metaplasia / Q000517:prevention & control; D008875:Middle Aged; D016017:Odds Ratio; D011230:Precancerous Conditions / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D012907:Smoking / Q000009:adverse effects*
D000970:Antineoplastic Agents; D000781:Anethole Trithione