A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia

Stephen Lam, Calum MacAulay, Jean C. Le Riche, Yulia Dyachkova, Andy Coldman, Martial Guillaud, Ernest Hawk, Marie Odile Christen, Adi F. Gazdar

Research output: Contribution to journalArticle

120 Citations (Scopus)

Abstract

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. Chisquare 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. Conclusion: Our results suggest that, in smokers, ADT is a potentially efficacious chemoprevention agent for lung cancer.

Original languageEnglish (US)
Pages (from-to)1001-1009
Number of pages9
JournalJournal of the National Cancer Institute
Volume94
Issue number13
StatePublished - Jul 3 2002

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Placebos
Bronchoscopy
Confidence Intervals
Lung Neoplasms
Biopsy
anethole
Chemoprevention
Disease Progression
Biomarkers
Smoking
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Lam, S., MacAulay, C., Le Riche, J. C., Dyachkova, Y., Coldman, A., Guillaud, M., ... Gazdar, A. F. (2002). A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia. Journal of the National Cancer Institute, 94(13), 1001-1009.

A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia. / Lam, Stephen; MacAulay, Calum; Le Riche, Jean C.; Dyachkova, Yulia; Coldman, Andy; Guillaud, Martial; Hawk, Ernest; Christen, Marie Odile; Gazdar, Adi F.

In: Journal of the National Cancer Institute, Vol. 94, No. 13, 03.07.2002, p. 1001-1009.

Research output: Contribution to journalArticle

Lam, S, MacAulay, C, Le Riche, JC, Dyachkova, Y, Coldman, A, Guillaud, M, Hawk, E, Christen, MO & Gazdar, AF 2002, 'A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia', Journal of the National Cancer Institute, vol. 94, no. 13, pp. 1001-1009.
Lam S, MacAulay C, Le Riche JC, Dyachkova Y, Coldman A, Guillaud M et al. A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia. Journal of the National Cancer Institute. 2002 Jul 3;94(13):1001-1009.
Lam, Stephen ; MacAulay, Calum ; Le Riche, Jean C. ; Dyachkova, Yulia ; Coldman, Andy ; Guillaud, Martial ; Hawk, Ernest ; Christen, Marie Odile ; Gazdar, Adi F. / A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia. In: Journal of the National Cancer Institute. 2002 ; Vol. 94, No. 13. pp. 1001-1009.
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abstract = "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. Chisquare 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. Conclusion: Our results suggest that, in smokers, ADT is a potentially efficacious chemoprevention agent for lung cancer.",
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AU - Dyachkova, Yulia

AU - Coldman, Andy

AU - Guillaud, Martial

AU - Hawk, Ernest

AU - Christen, Marie Odile

AU - Gazdar, Adi F.

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N2 - 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. Chisquare 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. Conclusion: Our results suggest that, in smokers, ADT is a potentially efficacious chemoprevention agent for lung cancer.

AB - 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. Chisquare 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. Conclusion: Our results suggest that, in smokers, ADT is a potentially efficacious chemoprevention agent for lung cancer.

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