A Randomized Phase II Chemoprevention Trial of 13-CIS Retinoic Acid with Or without α Tocopherol or Observation in Subjects at High Risk for Lung Cancer

• Published in: Cancer prevention research (Philadelphia, Pa.) Vol. 2; no. 5; pp. 440 - 449
• Main Authors: Kelly, Karen, Kittelson, John, Franklin, Wilbur A., Kennedy, Timothy C., Klein, Catherine E., Keith, Robert L., Dempsey, Edward C., Lewis, Marina, Jackson, Mary K., Hirsch, Fred R., Bunn, Paul A., Miller, York E.
• Format: Journal Article
• Language: English
• Published: United States 01.05.2009
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - therapeutic use; Bronchoscopy; Female; Humans; Isotretinoin - therapeutic use; Lung - drug effects; Lung Neoplasms - prevention & control; Male; Middle Aged; Neoplasm Recurrence, Local - prevention & control; Risk Factors; Smoking - adverse effects; Tocopherols - therapeutic use
• ISSN: 1940-6207; 1940-6215; 1940-6215
• DOI: 10.1158/1940-6207.CAPR-08-0136

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 α 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 α tocopherol (13-cis RA/α 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 obervations/13-cis RA/13-cis RA/α 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/α 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 α tocopherol did not affect toxicity.