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

Authors' Affiliations: ¹ Division of Medical Oncology, Departments of ² Biostatistics and ³ Pathology, ⁴ Division of Pulmonary Sciences and Critical Care Medicine at the University of Colorado at Denver, ⁵ Denver Veterans Affairs Medical Center, and ⁶ HealthOne, University of Colorado Cancer Center, Denver, Colorado

Requests for reprints: York E. Miller, Pulmonary 111A, Denver VAMC, 1055 Clermont Street, Denver, CO 80220. Phone: 303-393-2869; Fax: 303-393-4639; E-mail: york.miller{at}uchsc.edu.

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

Key Words: chemoprevention • Ki-67 • lung cancer