title: A randomized phase II chemoprevention trial of 13-CIS retinoic acid with or without alpha tocopherol or observation in subjects at high risk for lung cancer.
abstract: No chemoprevention strategies have been proven effective for lung cancer. We evaluated the effect of 13-cis retinoic acid (13-cis RA), with or without alpha tocopherol, as a lung cancer chemoprevention agent in a phase II randomized controlled clinical trial of adult subjects at high risk for lung cancer as defined by the presence of sputum atypia, history of smoking, and airflow obstruction, or a prior surgically cured nonsmall cell lung cancer (disease free, >3 years). Subjects were randomly assigned to receive either 13-cis RA, 13-cis RA plus alpha tocopherol (13-cis RA/alpha toco) or observation for 12 months. Outcome measures are derived from histologic evaluation of bronchial biopsy specimens obtained by bronchoscopy at baseline and follow-up. The primary outcome measure is treatment "failure" defined as histologic progression (any increase in the maximum histologic score) or failure to return for follow-up bronchoscopy. Seventy-five subjects were randomized (27/22/26 to observations/13-cis RA/13-cis RA/alpha toco); 59 completed the trial; 55 had both baseline and follow-up bronchoscopy. The risk of treatment failure was 55.6% (15 of 27) and 50% (24 of 48) in the observation and combined (13 cis RA plus 13 cis RA/alpha toco) treatment arms, respectively (odds ratio adjusted for baseline histology, 0.97; 95% confidence interval, 0.36-2.66; P = 0.95). Among subjects with complete histology data, maximum histology score in the observation arm increased by 0.37 units and by 0.03 units in the treated arms (difference adjusted for baseline, -0.18; 95% confidence interval, -1.16 to 0.81; P = 0.72). Similar (nonsignificant) results were observed for treatment effects on endobronchial proliferation as assessed by Ki-67 immunolabeling. Twelve-month treatment with 13-cis RA produced nonsignificant changes in bronchial histology, consistent with results in other trials. Agents advancing to phase III randomized trials should produce greater histologic changes. The addition of alpha tocopherol did not affect toxicity.
authors.affiliation: Pulmonary 111A, Denver VA Medical Center, 1055 Clermont Street, Denver, CO 80220, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Kelly
authors.forename: John
authors.initials: J
authors.lastname: Kittelson
authors.forename: Wilbur A
authors.initials: WA
authors.lastname: Franklin
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Kennedy
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Klein
authors.forename: Robert L
authors.initials: RL
authors.lastname: Keith
authors.forename: Edward C
authors.initials: EC
authors.lastname: Dempsey
authors.forename: Marina
authors.initials: M
authors.lastname: Lewis
authors.forename: Mary K
authors.initials: MK
authors.lastname: Jackson
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bunn
authors.forename: York E
authors.initials: YE
authors.lastname: Miller
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001999:Bronchoscopy; D005260:Female; D006801:Humans; D015474:Isotretinoin / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects; D008175:Lung Neoplasms / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D024505:Tocopherols / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D015474:Isotretinoin; D024505:Tocopherols