Chemoprevention Strategies for NSCLC Exposure to tobacco smoke is associated with 85% of clinical lung cancers seen in the United States, a fact that enables researchers to readily identify groups of patients in whom studies of chemopreventive agents may be conducted. Dr. Waun Ki Hong, from M.D. Anderson Cancer Center, Houston, Texas, is regarded as a leading authority in the chemoprevention of aerodigestive cancers. He presented an important update on state-of-the-art techniques in lung cancer chemoprevention, which was given during the first plenary session at the 9th World Conference on Lung Cancer.[6] Retinoids are a rational choice as chemoprevention agents because they have been shown to reverse epithelial keratinization in model systems, thereby inhibiting carcinogenesis and tumor growth. The hypothesis is that bronchial metaplasia in active smokers can be reversed by retinoid therapy. Studies using 13-cis retinoic acid or 4-HPR did not show significant reductions in the metaplasia index in smokers. However, using 13-cis retinoic acid, there were highly significant reductions in the metaplasia index of patients who had stopped smoking. It is possible that the confounding effects of continued smoking, and the interactions between tobacco smoke and retinoids, make these compounds less effective in active smokers than in former smokers or those who never smoked. Dr. Hong also reviewed the evidence to date on the presence (or absence) of retinoids in active smokers, details of which are highly consistent with research results that show retinoids to have very poor activity as chemopreventive agents in active smokers. Data from the EUROSCAN trial, looking at the ability of retinol to prevent second primary cancers, were recently reported as negative findings.[7] Dr. Hong also reported that the early data from the Intergroup trial of 13-cis retinoic acid, used to prevent second primaries in resected, stage-1 lung cancer patients, did not show benefit. In fact, in the subgroup of patients who continue to smoke, the agent may exert a detrimental effect, leading to enhanced local regional recurrence. What therapy is then available and effective for former smokers? Although there are extensive programs designed to convince patients to stop smoking, the question remains as to whether there any interventions to reverse the malignant phenotype that may be present due to the damage done by years of smoking, prior to cessation. This is not a trivial group; in the United States, this group includes 45 million individuals. Retinoid therapy offers the theoretical opportunity to reverse defects in retinoid-signaling pathways that may be present in former smokers, as was discussed by Dr. Minna earlier in the session.[2] Investigators at M.D. Anderson Cancer Center are conducting a randomized, 3-arm, controlled trial of 13-cis retinoic acid + vitamin E vs 9-cis retinoic acid vs placebo. Molecular endpoints of LOH at 3p, 9p, and 17p, RAR-B abnormalities, genomic instability and Ki67 staining are being used as markers. Preliminary data were presented suggesting that this trial will be completed in the near future. The use of molecular endpoints allows the generation of data that could support a large, randomized, phase-3 trial of this strategy, in a group of former smokers. There are a number of newer compounds being tested that hold great promise as therapeutic agents, in addition to the retinoids. The epidermal growth-factor receptor tyrosine-kinase inhibitor, Iressa (ZD1839), will be compared with placebo and a farnesyl-transferase inhibitor, in subjects who are either former or current smokers, and outcomes will be measured with molecular endpoints. COX-2 inhibitors are also candidate chemopreventive agents, and are soon to be included in randomized trials. As of this point in the year 2000, there are no trials or data that support the use of any specific chemopreventive strategy in former smokers. Given that some trials have actually shown poorer outcomes with the use of chemopreventive strategies, such as the CARET trial with beta-carotene[8], it is important to continue to do randomized trials in this setting. October 2000 Source was lost. Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.